Method of treating cancer with a synergistic formulation

Abstract

Synergistic combinations of compounds useful for treating cancer. The combinations include, but are not limited to: (1) digoxin or digoxin derivatives in combination with (2) simvastatin, rosemary extract, turmeric extract, kava extract, 5-fluorouracil (5-FU), ginger extract, or combinations thereof in synergistically effective amounts; (1) kava extract in combination with (2) ginger extract or combinations thereof in synergistically effective amounts; (1) dihydromethysticin (DHM) in combination with (2) turmeric extract, 5-fluorouracil (5-FU), hibiscus extract, or combinations thereof in synergistically effective amounts; and (1) rosemary extract in combination with (2) actein, simvastatin, or combinations thereof in synergistically effective amounts.

Description

METHOD OF TREATING CANCER WITH A SYNERGISTIC FORMULATIONCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to, and is a non-provisional of, U.S. Patent Application 63 / 751,448 (filed January 30, 2025) the entirety of which is incorporated herein by reference.STATEMENT OF FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] This invention was made with government support under grant number GM113782 grant (SR) awarded by the National Institute of General Medical Sciences (NIGMS), which is a subdivision of the National Institutes of Health (NIH). The government has certain rights in the invention.BACKGROUND OF THE INVENTION

[0003] Colorectal cancer represents a serious problem, with estimates suggesting on the order of half a million people die from colon and rectal cancer each year. Early detection is key with treatments primarily involving surgery, chemotherapy and radiation therapy. Therapeutic regiments often include adjuvant therapy with FOLFOX (a combination of fluorouracil (5-FU), folinic acid and oxaliplatin), FOLFIRI (5-FU. folinic acid and irinotecan), and / or CAPOX (capecitabine and oxaliplatin). While these therapeutics are at least somewhat effective, there remains a need for improved therapeutics.

[0004] The discussion above is merely provided for general background information and is not intended to be used as an aid in determining the scope of the claimed subject matter.SUMMARY

[0005] This disclosure provides synergistic combinations of compounds useful for treating cancer. The combinations include, but are not limited to: (1) digoxin or digoxinderivatives in combination with (2) simvastatin, rosemary extract, turmeric extract, kava extract, 5 -fluorouracil (5-FU), ginger extract, or combinations thereof in synergistically effective amounts; (1) kava extract in combination with (2) ginger extract or combinations thereof in synergistically effective amounts; (1) dihydromethysticin (DHM) in combination with (2) turmeric extract, 5 -fluorouracil (5-FU), hibiscus extract, or combinations thereof in synergistically effective amounts; and (1) rosemary extract in combination with (2) actein, simvastatin, or combinations thereof in synergistically effective amounts.

[0006] Tn a first embodiment, a method for treating colorectal cancer in a patient is provided. The method comprising: administering to the patient a therapeutically effective amount of a combination of a rosemary extract and simvastatin, wherein the rosemary extract is an acetone extract of rosemary leaves comprising camosic acid, 12-O-methyl carnosic acid, and camosol, and wherein the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.8 when tested in an in vitro cell viability assay.

[0007] In a second embodiment, composition of matter is provided. The composition of matter comprising a combination of a rosemary extract and simvastatin, wherein the rosemary extract is an acetone extract of rosemary leaves comprising camosic acid, 12-O-methyl carnosic acid, and carnosol.

[0008] In a third embodiment, a method of synergistically inhibiting growth of colon adenocarcinoma cells is provided. The method comprising: contacting the colon adenocarcinoma cells with a combination of a rosemary extract and simvastatin, wherein the rosemary extract is an acetone extract of rosemary leaves comprising camosic acid, 12-O-methyl camosic acid, and carnosol, and wherein the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells as determined by Bliss independence analysis with an Observed / Expected viability ratio of less than 1.0 when tested in an in vitro cell viability assay.

[0009] In a fourth embodiment, a method of synergistically inhibiting growth of colon adenocarcinoma cells is provided. The method comprising: contacting the colon adenocarcinoma cells with a combination of a rosemary extract and simvastatin, wherein the combination exhibits excess growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells beyond the highest single agent (AHSA > 0) as determined by comparison to the most effective single agent selected from the rosemary extract and the simvastatin.

[0010] This brief description of the invention is intended only to provide a brief overview of subject matter disclosed herein according to one or more illustrative embodiments and does not serve as a guide to interpreting the claims or to define or limit the scope of the invention, which is defined only by the appended claims. This brief description is provided to introduce an illustrative selection of concepts in a simplified form that are further described below in the detailed description. This brief description is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used as an aid in determining the scope of the claimed subject matter. The claimed subject matter is not limited to implementations that solve any or all disadvantages noted in the background.DETAILED DESCRIPTION OF THE INVENTION

[0011] This disclosure presents a therapeutic method utilizing a first compound, in synergistic combination with one or more second compounds to effectively treat colon cancer and. in some embodiments, breast cancer. The approach leverages the synergistic effects of these compounds to target critical cancer pathways, enhance chemotherapy efficacy, and reduce treatment-related toxicity.

[0012] In one embodiment, the therapeutic method uses a synergistic combination of (1) digoxin (including its derivates) and (2) a synergistic additive selected from the group consisting of simvastatin, rosemary, turmeric, kava. 5 -fluorouracil (5-FU), ginger, and combinations thereof.

[0013] In another embodiment, the therapeutic method uses a synergistic combination of (1) kava and (2) ginger.

[0014] In another embodiment, the therapeutic method uses a synergistic combination of (1) dihydroxymethysticin (DHM) and (2) a synergistic additive selected from the group consisting of turmeric, 5-FU and hibiscus and combinations thereof.

[0015] In another embodiment, the therapeutic method uses a synergistic combination of (1) rosemary and (2) a synergistic additive selected from the group consisting of actein, simvastatin and combinations thereof.

[0016] In another embodiment, the therapeutic method uses a synergistic combination of (1) actein and (2) sulindac sulfide.

[0017] In another embodiment, the therapeutic method uses a synergistic combination of (1) unfiltered kava and (2) a synergistic additive selected from the group consisting of simvastatin, 5-FU, turmeric and combinations thereof.

[0018] To quantify the interaction between two compounds, a combination index (CI) was calculated using an ICso-shift (dose- additivity) method based on Chou-Talalay principles (Chou and Talalay, Advances in Enzyme Regulation, v. 22, 1984, pp. 27-55; Soriano et al., Cancer Research 59:6178-6184, 1999); Planta Medica 72:1200-1206, 2006). This method is a widely recognized method of quantifying drug synergy. In this approach, CI is calculated as:

[0019] CI and its corresponding effects are as follows: >1.3 is antagonism; 1.1-1.3 is moderate antagonism; 0.9-1.1 is an additive effect; 0.8-0.9 is a slight synergism; 0.6-0.8 is a moderate synergism; and <0.6 is a strong synergism.

[0020] For colon cancer assays, HT29 (HT29 colon adenocarcinoma cells (TP53 mutant; similar to enterocytes from the small intestine) colon cancer cells were obtained from the American Type Culture Collection (ATCC). For breast cancer assays (Columbia: MDA-MB-453 (ER-)) or MCF7 (ER+) breast cancer cells were used. Cells were treated at multiple concentrations alongside a solvent control. Cells were exposed to increasing concentrations for 96 h and the number of viable cells determined by the MTT assay.<0021] Digoxin Combinations

[0022] In one embodiment, the first compound has a structure of Formula A, wherein R1is OH and R2is H (digoxin) or R1and R2are both H (digitoxin). As used herein, the phrase “digoxin derivative” refers to any compound structurally related to digitoxin, including modifications to its glycoside or aglycone portions, its metabolic products, and synthetic analogs that retain or enhance digoxin therapeutic efficacy. Digoxin IC50 values cited herein were approximately 0.025-0.0725 pg / mL across experiments.

[0023] Digoxin + simvastatin: colon cancer and ER+breast cancer

[0024] The combination of digoxin and simvastatin is useful for treating colon cancer.

[0025] When tested on HT29 cells, the IC50 values for digoxin and simvastatin alone were approximately 0.0725 pg / mL (0.0928 pM) and 6 pg / mL (14.3 pM), respectively. As shown in Table 1A and Table IB, digoxin enhances the growth inhibitory effect of simvastatin on the HT29 human colon adenocarcinoma cells.<

[0026] When tested on HT29 colon cancer cells, the CI for the combination of digoxin and simvastatin are shown in Table IB.

[0027] In one embodiment, a composition comprising digoxin and simvastatin is delivered to a patient in need of treatment for colon cancer such that the cancer cells are contacted with both digoxin and simvastatin in a particular concentration ratio that produces a synergy. In one embodiment, the concentration ratio (digoxin: simvastatin)may be about equal to any of the concentration ratios shown in Table IB wherein the CI is < 0.8; < 0.7 or < 0.5. In one such embodiment, the concentration ratio is about 0.04:10.

[0028] Digoxin + Simvastatin (Breast Cancer)

[0029] Digoxin enhances the growth of inhibitory effect of simvastatin in ER+MCF7 breast cancer cells.

[0030] The combination of digoxin and simvastatin is useful for inhibiting growth of ER+breast cancer cells. ER+ MCF7 human breast cancer cells were treated with digoxin and simvastatin at the concentrations shown in Table 1C, generating 25 total combinations. Cell viability was determined after 96 hours using the MTT assay. When tested in ER+MCF7 cells, neither digoxin nor simvastatin achieved 50% growth inhibition (IC50) within the tested concentration range. As shown in Table 1C, digoxin enhanced the growth inhibitory effect of simvastatin in ER+MCF7 cells. For example, at simvastatin 0.8 pg / mL, cell viability decreased from 108.19% with simvastatin alone to 101.62%, 87.74%, and 79.19% in the presence of digoxin at 0.01. 0.04, and 0.1 pg / mL, respectively (p<0.01).

[0031] Because IC50 values were not reached for either agent in MCF7 cells within the tested concentration ranges, synergy was quantified using two complementary models: (1) a Bliss Independence Model wherein synergy is indicated when the observed effect exceeds the expected effect under independence and (2) a Highest Single Agent (HSA) Model wherein synergy is indicated when the combination effect exceeds the effect of the most active single agent alone. With regard to the Bliss independence model, this can be expressed as (la) ABliss (excess inhibition) > 0, or equivalently as (lb) Bliss Ratio (Observed / Expected) < 1.0. With regard to the HAS model, synergy is indicated when AHSA (excess inhibition) > 0. Results from both models are presented in Tables ID-1 and ID-2. Positive ABliss and / or AHSA values indicate synergistic interaction.pg / mL with simvastatin 0.8-30 pg / mL, with AHSA up to +0.2187 (simvastatin 4 + digoxin 0.1). These results demonstrate that the combination consistently outperforms both single agents, with the Bliss Ratio (Observed / Expected) < 1.0 for synergistic combinations.

[0033] In one embodiment, a composition comprising digoxin and simvastatin is delivered to a patient in need of treatment for breast cancer such that the cancer cells are contacted with both digoxin and simvastatin in a particular concentration ratio that produces a synergy. In one embodiment, the concentration ratio (digoxin: simvastatin) may be about equal to any of the concentration ratios shown in Table ID-1 wherein the ABliss score is > 0. In one such embodiment, the concentration ratio is about 0.1:0.8; 0.1 :4; 0.1 : 10 or 0.1 :30. In one embodiment, the concentration ratio (digoxin:simvastatin) may be about equal to any of the concentration ratios shown in Table ID-2 wherein the AHSA is > 0 or > 0.1. In one such embodiment, the concentration ratio is about 0.1:0.8; 0.1:4; 0.1:10 or 0.1:30.

[0034] Digoxin + rosemary

[0035] The IC50 values for rosemary and digoxin alone were approximately 4 pg / ml and 0.072 pg / ml (0.092 pM), respectively, on HT29 (TP53 mutant) colon cancer cells. As shown in Table 2A and Table 2B, rosemary and digoxin synergistically enhance the growth inhibitory effect on the human colon cancer cell line HT29.<0036] The CI values for the combination of digoxin and rosemary are shown in Table 2B.

[0037] In one embodiment, a composition comprising digoxin and rosemary is delivered to a patient in need of treatment for colon cancer such that the cancer cells are contacted with both digoxin and rosemary in particular concentration ratio that produces a synergy. In one embodiment, the concentration ratio (digoximrosemary) may be about equal to any of the concentration ratios shown in Table 2B wherein the CI is < 0.8, < 0.7. < 0.6 or < 0.5. In one such embodiment, the concentration ratio is about 0.02:10.

[0038] Digoxin + turmeric

[0039] The ICso values for digoxin and turmeric (95% curcuminoids; 74% curcumin), alone, were approximately 0.025 pg / ml and 4.2 pg / ml, respectively, onHT29 (TP53 mutant) colon cancer cells. As shown in Table 3 A and Table 3B, turmeric and digoxin synergistically enhance the growth inhibitory effect on the human colon cancer cell line HT29.<0040] The CI values for the combination of digoxin and turmeric are provided in Table 3B.

[0041] In one embodiment, a composition comprising digoxin and turmeric is delivered to a patient in need of treatment for colon cancer such that the cancer cells are contacted with both digoxin and turmeric in a particular concentration ratio the produces a synergy. In one embodiment, the concentration ratio (digoximturmeric) may be about equal to any of the concentration ratios shown in Table 3B wherein the CI is < 0.8; < 0.7, <0.6, < 0.5 or < 0.4. In one such embodiment, the concentration ratio is about 0.02:10.

[0042] Digoxin + kava

[0043] The ICso values for digoxin and kava, alone, were approximately 0.072 pg / ml and 25 pg / ml, respectively, on HT29 (TP53 mutant) colon cancer cells. Table 4A shows the results of cell viability assays as concentrations of kava and / or digoxin were altered. <0044] Table 4B depicts CI values at different concentrations of digoxin and kava.<to a patient in need of treatment for colon cancer such that the cancer cells are contacted with both digoxin and kava in a particular concentration ratio that produces a synergy. In one embodiment, the concentration ratio (digoximkava) may be about equal to any of the concentration ratios shown in Table 4B wherein the CI is < 0.8; < 0.7; < 0.6; < 0.5; < 0.4; <0.3, <0.2 or < 0.1. In one such embodiment, the concentration ratio is about 0.1:30.

[0046] Digoxin + 5-FU

[0047] The IC50 values for digoxin and 5-FU, alone, were approximately 0.092 pg / ml and 1.778 pg / ml, respectively, on (TP53 mutant) HT29 colon cancer cells. Table 5A shows the results of cell viability assays as concentrations of 5-FU and / or digoxin were altered. As shown in Table 5 A and Table 5B, 5-FU and digoxin synergistically enhance the growth inhibitory effect on the human colon cancer cell line HT29.to a patient in need of treatment for colon cancer such that the cancer cells are contacted with both digoxin and 5-FU in a particular concentration ratio that produces a synergy. In one embodiment, the concentration ratio (digoxin:5-FU) may be about equal to any of the concentration ratios shown in Table 5B wherein the CI is < 0.8; < 0.7; < 0.6; < 0.5; < 0.4 or <0.3. In one such embodiment, the concentration ratio is about 0.1:5.

[0049] Digoxin + ginger

[0050] The IC50 values for digoxin and ginger, alone, were approximately 0.041 pg / ml and 13 pg / ml, respectively, on HT29 (TP53 mutant) colon cancer cells. As shown in Table 6A and Table 6B, ginger and digoxin synergistically enhance the growth inhibitory effect on the human colon cancer cell line HT29.

[0051] In one embodiment, a composition comprising digoxin and ginger is delivered to a patient in need of treatment for colon cancer such that the cancer cells are contacted with both digoxin and ginger in a particular concentration ratio that produces a synergy. In one embodiment, the concentration ratio (digoximginger) may be about equal to any of the concentration ratios shown in Table 6B wherein the CI is < 0.8. In one such embodiment, the concentration ratio is about 0.04:0.8.

[0052] Kava + ginger

[0053] The IC50 values for kava and ginger alone were approximately 7 pg / ml and 34 pM, respectively, on H29 colon cancer cells. As shown in Table 7A and Table 7B, ginger and kava synergistically enhance the growth inhibitory effect on the human colon cancer cell line HT29.

[0054] In one embodiment, a composition comprising ginger and kava is delivered to a patient in need of treatment for colon cancer such that the cancer cells are contacted with both ginger and kava in a particular concentration ratio that produces a synergy. In one embodiment, the concentration ratio (ginger:kava) may be about equal to any of the concentration ratios shown in Table 7B wherein the CI is < 0.8; < 0.7 or < 0.6. In one such embodiment, the concentration ratio is about 10:2.

[0055] DHM + turmeric

[0056] The IC50 values for DHM and turmeric alone against HT29 colon cancer cells were approximately 30 pg / mL and 3.9 pg / mL, respectively. Cell viability was measured after 96 hours. As shown in Table 8A and Table 8B, DHM and turmeric synergistically enhance the growth inhibitory effect on the human colon cancer cell line HT29.delivered to a patient in need of treatment for colon cancer such that the cancer cells are contacted with both DHM and turmeric in a particular concentration ratio to produce a synergy. In one embodiment, the concentration ratio (DHM:turmeric) may be about equal to any of the concentration ratios shown in Table 8B wherein the CI is < 0.8; < 0.7 or < 06. In one embodiment, the concentration ratio is about 2:3.

[0058] DHM + 5-FU

[0059] The IC50 values for DHM and 5 -fluorouracil (5-FU) alone against HT29 colon cancer cells were approximately 35 pg / mL and 1 pg / mL, respectively. Cell viability was measured after 96 hours. Data points represent mean values from replicate experiments. As shown in Table 9A and Table 9B, DHM and 5-FU synergistically enhance the growth inhibitory effect on the human colon cancer cell line HT29.<

[0060] In one embodiment, a composition comprising DHM and 5-FU is delivered to a patient in need of treatment for colon cancer such that the cancer cells are contacted with both DHM and 5-FU in a particular concentration ratio to produce a synergy. In one embodiment, the concentration ratio (DHM: 5-FU) may be about equal to any of the concentration ratios shown in Table 9B wherein the CI is < 0.8; < 0.7; < 0.6; < 0.5; < 0.4 or < 0.3. In one such embodiment, the concentration ratio is about 10:0.02.

[0061] DHM + hibiscus

[0062] The IC50 values for DHM and hibiscus, alone, against HT29 colon cancer cells were approximately 14 pg / mL and 40 pg / mL, respectively. As shown in Table 10A and Table 10B, DHM and hibiscus synergistically enhance the growth inhibitory effect on the human colon cancer cell line HT29.

[0063] In one embodiment, a composition comprising DHM and hibiscus is delivered to a patient in need of treatment for colon cancer such that the cancer cells are contacted with both DHM and hibiscus in a particular concentration ratio to produce a synergy. In one embodiment, the concentration ratio (DHM:hibiscus) may be about equal to any of the concentration ratios shown in Table 10B wherein the CI is < 0.8; < 0.7; < 0.6, < 0.5 or < 0.4. In one such embodiment, the concentration ratio is about 2:10.

[0064] Rosemary + actein

[0065] The IC50 values for Rosemary and actein, alone, against HT29 colon cancer cells were approximately 13.2 pg / mL and 22.3 pg / mL, respectively. As shown in Table 11 A and Table 1 IB, actein and rosemary synergistically enhance the growth inhibitory effect on the human colon cancer cell line HT29.

[0066] In one embodiment, a composition comprising rosemary and actein is delivered to a patient in need of treatment for colon cancer such that the cancer cells are contacted with both rosemary and actein in a particular concentration ratio to produce a synergy. In one embodiment, the concentration ratio (acteimrosemary) may be about equal to any of the concentration ratios shown in Table 11B wherein the CI is < 0.8; < 0.7; < 0.6; < 0.5; < 0.4 or < 0.3. In one such embodiment, the concentration ratio is about 30:20.

[0067] Rosemary + Simvastatin

[0068] The IC50 values for rosemary and simvastatin, alone, against HT29 colon cancer cells were approximately 16.9 pg / mL and 3.32 pg / mL, respectively. As shown in Table 12A and Table 12B, simvastatin and rosemary synergistically enhance the growth inhibitory effect on the human colon cancer cell line HT29.0069] Synergy Analysis: The synergistic interaction between rosemary extract and simvastatin was evaluated using multiple complementary analytical methods:

[0070] IC50-Shift Screening Analysis: For preliminary synergy assessment, a combination index (CI) was calculated based on IC50 shifts using the formula: CI = [IC5o(rosemary in combo) / IC5o(rosemary alone)] + [ICso simvastatin in combo) / IC5o(simvastatin alone)]. CI < 1.0 indicates synergy. Representative CI values are shown in Table 12B, with notable synergy observed at multiple concentration pairs (e.g„ Ros 10 + Sim 2: CI = 0.6543: Ros 10 + Sim 4: CI = 0.7124).

[0071] Multiple combinations demonstrate synergistic activity. Notable combinations include rosemary (10 pg / mL) combined with simvastatin at 2, 4, or 10 pg / mL, which provide CI values of 0.6543, 0.7124, and 0.5876. respectively. The combination of rosemary (10 pg / mL) and simvastatin (10 pg / mL) produced the lowest CI value at this rosemary concentration (CI = 0.5876), with 15.99% cell viability (84% growth inhibition). At higher rosemary concentrations, the combination of rosemary (30 pg / mL) and simvastatin (10 pg / mL) exhibited the strongest synergy overall (CI = 0.3987).

[0072] Bliss Independence Model: Synergy was further confirmed using Bliss independence analysis based on cell viability (%). For each dose pair, the expected viability under independence was calculated as: Expected viability (%) = [Viability_rosemary x Viability_simvastatin] / 100. Synergy is indicated when the observed viability is lower than expected (i.e., excess inhibition; Observed / Expected < 1.0).

[0073] Using Table 12A single-agent viabilities (rosemary alone: 0.8— >88.31%, 2— >87.27%, 10— >75.15%, 30^27.00%; simvastatin alone: 0.8^95.11%, 2^65.87%, 4— >18.33%, 10— >25.98%), representative Bliss results include: (1) Rosemary 10 pg / mL + Simvastatin 2 pg / mL: Expected 49.50%, Observed 22.90% (Observed / Expected = 0.463) indicates synergy (2) Rosemary 10 pg / mL + Simvastatin 0.8 pg / mL: Expected 71.48%, Observed 48.37% (0.677) indicates synergy (3) Rosemary 30 pg / mL + Simvastatin 0.8 pg / mL: Expected 25.68%, Observed 17.24% (0.671) indicates synergy (4) Rosemary 2 pg / mL + Simvastatin 2 pg / mL: Expected 57.48%, Observed 52.75% (0.918) indicates mild synergy

[0074] Bliss independence analysis was applied to selected representative dose pairs to demonstrate and confirm synergistic interaction, without requiring characterization of all possible concentration combinations.

[0075] Highest Single Agent (HSA) Model: Synergy was further validated by calculating excess inhibition beyond the best single agent: AHSA = Inhibition_combo -max(Inhibition_rosemary, Inhibition_simvastatin). The HSA model is a non-parametric reference framework that does not assume dose additivity and serves as an independent comparator to Ci-based analyses. AHSA > 0 indicates synergy. Representative results calculated from Table 12A single-agent and combination viabilities include Ros 10 + Sim 2 (AHSA = +42.97%) and Ros 2 + Sim 2 (+13.12%).

[0076] All three independent analytical methods demonstrated synergistic interaction between rosemary extract and simvastatin, confirming that the combination produces greater growth inhibition than predicted by additive models or achieved by either agent alone.

[0077] In one embodiment, the rosemary extract comprises approximately 40-60 % carnosic acid, as characterized by liquid chromatography. In another embodiment, the rosemary extract is an acetone extract of rosemary leaves comprising 48+10 % carnosic acid, 8+5 % 12-O-methyl carnosic acid, and 3+2 % camosol, as determined by liquid chromatography. Percentages are area under the peak. In one embodiment, the rosemary extract is an extract described in United States Patent 5,859,293, the content of which is hereby incorporated by reference.

[0078] Actein + Sulindac Sulfide

[0079] Actein combined with sulindac sulfide was evaluated using a non-constant ratio matrix design. HT29 cells were treated with actein and sulindac sulfide at the concentrations shown in Table 13A, generating 25 total combinations. Cell viability was determined after 96 hours using the MTT assay.

[0080] Because sulindac sulfide produced a non-monotonic response (viability >100% at some doses), median-effect (Chou-Talalay) fitting was not valid and IC50 values were not reliably defined, making IC50-shift calculations unsuitable. Accordingly, synergy was assessed using the Bliss Independence Model, expressed as a ratio of Observed to Expected viability under independence. Under this model: Bliss Ratio (Observed / Expected) < 1.0 indicates synergy; Bliss Ratio = 1.0 indicates additivity; Bliss Ratio > 1.0 indicates antagonism.

[0081] As shown in Table 13A and Table 13B, actein and sulindac sulfide synergistically enhance the growth inhibitory effect on the human colon cancer cell line HT29.

[0082] The combination of actein (30 pg / mL) and sulindac sulfide (25 pg / mL) produced 28.50% cell viability (71.5% growth inhibition). This represents a marked enhancement over actein alone (41.44% viability; 58.6% inhibition), corresponding to an additional 12.9% inhibition. Using the Bliss Independence Model, the Bliss Ratio (Observed / Expected) for this combination was 0.69, indicating synergistic activity.<0083] Actein (30 pg / mL) and sulindac sulfide (25 pg / mL) gave a Bliss Ratio = 0.69, demonstrating synergistic activity. In one embodiment, a composition comprising actein and sulindac sulfide is delivered to a patient in need of treatment for colon cancer such that the cancer cells are contacted with both actein and sulindac sulfide in a particular concentration ratio to produce synergistic activity, as assessed by a Bliss Ratio (Observed / Expected) < 1.0. In one embodiment, the concentration ratio (actein: sulindac sulfide) is about 30:25.

[0084] Unfiltered kava + simvastatin

[0085] The IC50 values for unfiltered kava and simvastatin alone, against HT29 colon cancer cells were approximately 19 pg / mL and 6 pg / mL, respectively. As shown in Table 14A and Table 14B, unfiltered kava and simvastatin synergistically enhance the growth inhibitory effect on the human colon cancer cell line HT29.simvastatin is delivered to a patient in need of treatment for colon cancer such that the cancer cells are contacted with both unfiltered kava and simvastatin in a particular concentration ratio to produce a synergy. In one embodiment, the concentration ratio (unfiltered kava: simvastatin) may be about equal to any of the concentration ratios shown in Table 14B wherein the CI is < 0.8; < 0.7; < 0.6; < 0.5; < 0.4 or < 0.3. In one such embodiment, the concentration ratio is about 2:2.

[0087] Unfiltered kava + 5-FU

[0088] The IC50 values for unfiltered kava and 5-FU alone, against HT29 colon cancer cells were approximately 40 pg / mL and 1.6 pg / mL, respectively. As shown in Table 15A and Table 15B, unfiltered kava and 5-FU synergistically enhance the growth inhibitory effect on the human colon cancer cell line HT29.0089] Unfiltered kava (0.8 pg / mL) and 5-FU (2 pg / mL) had a CI of 0.75 indicating a moderate synergy. Unfiltered kava (30 pg / mL) and 5-FU (2 pg / mL) had a CI of 0.3 indicating a strong synergy.delivered to a patient in need of treatment for colon cancer such that the cancer cells are contacted with both unfiltered kava and 5-FU in a particular concentration ratio to produce a synergy. In one embodiment, the concentration ratio (unfiltered kava:5-FU) may be about equal to any of the concentration ratios shown in Table 15B wherein the CI is < 0.8; < 0.7; < 0.6; < 0.5 or < 0.4. In one such embodiment, the concentration ratio is about 30:2.

[0091] Unfiltered kava + turmeric

[0092] The IC50 values for unfiltered kava and turmeric alone, against HT29 colon cancer cells were approximately 40 pg / mL and 1.6 pg / mL, respectively. As shown inTable 16A and Table 16B, unfiltered kava and turmeric synergistically enhance the growth inhibitory effect on the human colon cancer cell line HT29.

[0093] In one embodiment, a composition comprising unfiltered kava and turmeric is delivered to a patient in need of treatment for colon cancer such that the cancer cells are contacted with both unfiltered kava and turmeric in a particular concentration ratio to produce a synergy. In one embodiment, the concentration ratio (unfiltered kava:turmeric) may be about equal to any of the concentration ratios shown in Table 16B wherein the CI is < 0.8; < 0.7; < 0.6 or < 0.5. In one such embodiment, the concentration ratio is about 2:2.

[0094] Methods of Treatment

[0095] The disclosed combinations may be used as a preventative to treat colon cancer cells and / or precancerous cells. In one embodiment, the disclosed methods orcompositions are used on a subject that has been diagnosed with colon cancer and / or colorectal cancer. The combinations may be administered orally (e.g. as an oral supplement) or topically (e.g. a liquid or cream administered to the colon). The combinations may be administered parenterally (intravenously, intramuscularly, subcutaneously, etc.)

[0096] In any of the aforementioned treatment methods, the composition may be formulated as a solid, cream, gel, anal suppository. The composition may be incorporated into a device that is inserted into an oral cavity or an anal cavity, or placed in contact with the skin (e.g. an adhesive patch). The composition may also be formulated as a tablet, a foam, a spray, a film, a sponge, an emulsion, a solution, a nanofiber, a suspension, a particle, a nanoparticle, a bio-adhesive, or an oral rinse. The two compounds in the composition may be delivered simultaneously (e.g. as a single composition) or sequentially (e.g. as two separate compositions delivered in a relatively short period of time) provided both compounds are simultaneously present in a patient’ s body.

[0097] The composition may be co-formulated with one or more of a lipophilic carrier, a hydrophilic carrier, a muco-adhesive agent, a solubilizing agent, a stabilizer, an emulsifier, a buffer, a lubricant and / or a filler. A lipophilic carrier is a substance that dissolves in fats, oils and lipids. Examples include mineral oil, olive oil, caprylic / capric triglyceride, medium-chain triglycerides (MCT), castor oil, mineral oil, lechithin, vegetable oils, corn oil, sesame oil, ethyl oleate, oleic acid. A hydrophilic carrier is a substance that dissolves in water. Examples include water, glycerin, propylene glycol, ethanol, hydroxypropyl methylcellulose (HPMC) and polyethylene glycol (PEG). A muco-adhesive agent is a composition that helps adhere to mucosal surfaces. Examples include carbopol, chitosan, hyaluronic acid, sodium alginate, hydroxypropyl methylcellulose (HPMC), poly(acrylic acid), sodium carboxymethylcellulose, hydroxypropyl cellulose. A solubilizing agent is a substance that aids in dissolution. Examples include polysorbates (e.g. polysorbate 80), cyclodextrins, polyethylene glycol (PEG), PEG-40 hydrogenated castor oil, propylene glycol, ethanol, cremophor EL,sodium lauryl and sulfate. A stabilizer helps maintain stability of the composition.Examples include lechithin, sodium stearoyl lactylate, polysorbates (Tween 20, Tween 80, polysorbate 60), lecithin, sodium citrate, tris buffer, sodium metabisulfite, ascorbic acid, Ethylenediaminetetraacetic acid (EDTA), citric acid, butylated hydroxytoluene (BHT), tocopherols. Examples of emulsifiers include polysorbate 80, lecithin, sodium lauryl sulfate, cetyl alcohol, sorbitan monooleate and polyethylene glycol stearate. A buffer is a compound that maintains the pH of the composition. Examples include phosphate buffer (e.g. sodium phosphate), citrate buffer (e.g. citric acid), carbonate buffer (e.g. sodium bicarbonate), acetate buffer, tris buffer, HEPES buffer. A lubricant is a compound that reduces friction. Examples include silicone oil, glycerin, mineral oil, magnesium stearate, talc, stearic acid, stearic acid, calcium stearate, polyethylene glycol and colloidal silicon dioxide. A filler is a compound that adds bulk to the composition. Examples include microcrystalline cellulose, lactose, starch, calcium phosphate, maltodextrin, sorbitol and dicalcium phosphate.

[0098] Materials:

[0099] Digoxin, simvastatin, 5-FU and sulindac sulfide were obtained from Sigma Aldrich (St. Louis, MO). Dihydroxymethysticin (DHM) (> / = 85 wt%) was purchased from Chromadex (CA). DHM is a kavalactone from kava.

[0100] Rosemary was obtained from Naturex, Inc. (South Hackensack, NJ) as rosemary extract (Number: 141804; carnosic acid 50%). To prepare the rosemary extract, rosemary was collected from Morocco. By HPLC analysis, the main components of the extract are carnosic acid (48%), 12-O-methyl carnosic acid (8%), and camosol (3%). The procedure to prepare the extract is as follows: rosemary leaf was first ground into small particles, extracted with acetone at room temperature, filtered and concentrated under reduced pressure, then treated with acid and base. The acid insoluble substances, which include carnosic acid and carnosol, as well as carnosic derivatives, were precipitated, separated from liquid and dried in a vacuum oven to obtain the final product.

[0101] Hibiscus: Two sets of Hibiscus tiliaceus samples were collected during fieldwork for use in this analysis. Collections made in Pohnpei and Kosrae consisted ofH. tiliaceus mucilage and sap obtained from fresh stem barkwood, which was harvested using traditional methods of preparation. An additional collection of stem bark was obtained from Pohnpei for comparison of phytochemistry and activity with the mucilage / sap samples. The samples were frozen prior to being returned to the laboratory. All samples were frozen at -80° Celsius and then lyophilized to eliminate water content.

[0102] Hibiscus tiliaceus: The freeze-dried samples were ground to homogeneity and extracted in HPLC grade water as well as in 70% methanol / 30% water. All extracts were then evaporated to dryness under nitrogen gas. The crude methanolic extracts were further processed using solid phase extraction (SPE). Extracts were resuspended in 0.1% formic acid (aqueous), vortexed, sonicated, and loaded onto 1 ml Strata-X 33u Polymeric Reversed Phase SPE columns (Phenomenex, Torrance. CA) before being washed with 0.1% formic acid and eluted with 100% methanol. The resulting extracts and SPE extracts were stored at -20 °C prior to LC-MS analysis and bioassay. For hibiscus (Pohnpei) the starting material used for the methanol extracts and the extract yields were as follows: 3.8018 g H. tiliaceus sap / mucilage (Pohnpei) was frozen at -80° Celsius and lyophilized yielding 0.1734 g dry weight. We extracted 0.1375 g of freeze-dried H. tiliaceus (Pohnpei) sap / mucilage in 35 ml of 70% methanol for 60 min yielding 0.0778 g extract (0.566 g crude hibiscus methanol extract per 1.000 g starting material). For hibiscus (Kosrae): 3.1200 g H. tiliaceus sap / mucilage (Kosrae) was frozen at -80° Celsius and lyophilized yielding 0.3249 g dry weight. We extracted 0.2925 g of freeze-dried H. tiliaceus (Kosrae) sap / mucilage in 35 ml of 70% methanol for 60 min yielding 0.1426 g extract (0.488 g crude hibiscus methanol extract per 1.000 g starting material).

[0103] Solvent-solvent partitioning of Hibiscus tiliaceus mucilage / sap extract: The crude methanolic extracts of the Hibiscus tiliaceus sap / mucilage from Pohnpei and Kosrae were additionally subjected to a solvent- solvent partitioning scheme based on an increasing polarity gradient in order to identify active partitions. The crude extracts were suspended in HPLC grade water and sequentially partitioned with hexanes, chloroform, and butanol before being evaporated to dryness under nitrogen gas. The resultinghexanes, chloroform, butanol, and water residues were then submitted for LC-MS analysis and bioassay.

[0104] Actein was obtained from ChromaDex (Laguna Hills, CA, lot number 01355-101), purity 89% by HPLC, and from Planta Analytica (Danbury, CT, lot number PA-A-037), purity was over 95% by HPLC.

[0105] Turmeric (95 wt%) (Curcuma tonga L.) was purchased from Naturex (Avignon, France), Item #: 140500; the extract contained approximately 74 wt% curcumin (diferuloylmethane): typical range: curcumin (72-75 wt%); bisdemethoxycurcumin (3-4 wt%); demethoxycurcumin (16-17 wt%).

[0106] Ginger (Zingiber officinale Roscoe) root soft extract (20.5 wt% total pungent compounds calculated as gingerols and shogaol, Item #: 143010 from Naturex (Avignon, France); Extraction was with ethyl acetate and contained <5 wt% moisture and less than lOmg / kg residual ethyl acetate. Total gingerols + shogaols >20 wt% (HPLC), 6-gingerol (-8-10 wt%), 8-gingerol (-2-3 wt%), 10-gingerol (3-4 wt%), shogaols (-2-3 wt%), remainder being ginger polysaccharides, proteins, and native non-volatile constitutes. Kava (Piper methysticum G. Forst; 31.2 wt% kavalactones, Item #: 332679 from Naturex (Avignon, France) sometimes referred to as Nat-k. In one embodiment, the kava is dihydrokavain (40-45 wt%), kavain (15-20 wt%), dihydromethysticin (15-20 wt%), methysticin (>0 but < 5 wt%). yangonin (5-10 wt%), and demethoxyyangonin (3-5 wt%) with the remainder (about 70 wt%) being native kava constituents.

[0107] Unfiltered Kava: Three kava samples were obtained for use in this research. One kava was obtained from a market in Fiji, a second was packaged in Fiji ("Melanesian Fusion; variety: Madang Short; KL: 13% (HPLC); Kava Korporesen, Suva, Fiji Islands") and a third was grown in Hawaii ("Tuday; variety originally from Papua New Guinea). Aqueous kava (Piper methysticum) samples were prepared in the laboratory mimicking traditional kava preparation procedures. Ground kava samples were placed in a semi-porous cloth bag, which was soaked in HPLC grade water and slowly strained through the cloth for 10 min. The resulting cloudy suspension of the traditional kava aqueous extract was transferred to borosilicate glass jars for storage. All resulting kava aqueousextracts were then frozen at -80° Celsius and lyophilized to produce a dry powder which was used for phytochemical analysis by LC-MS as well as for bioassay experiments.

[0108] Detailed composition of unfiltered kava is described in L.S. Einbond et al., Traditional preparations of kava (Piper methysticum) inhibit the growth of human colon cancer cells in vitro. V. 24, 2017, pp. 1-13, the contents of which are incorporated herein by reference.

[0109] Briefly, unfiltered kava comprises about 11-25 % dihydromethysticin, about 50-74 % 7.8-dihydrokavain, about 6-10 % kavain, about 5-10 % 5,6,7, 8-tetrahydroyangonin, about 0.1-0.5 % 11 -hydroxy- 12-methoxydihydrokavain, about 0.1-1.0 % prenyl caffeate, about 0-1.0 % pinostrobin chaicone, about 0.1-3.0 % 11-methoxytetrahydroyangonin, about 0.1-1.0 % awaine, about 0.5-2.0 % methysticin, about 0.5-2.0 % yangonin, about 0.5-5.0 % desmethoxyyangonin, and about 0.1-1.0 % flavokawain B. Percentages are area under the peak. In one embodiment, the rosemary extract is an extract described in United States Patent 5,859,293, the content of which is hereby incorporated by reference.

[0110] Percentages were determined based on relative chromatographic peak area obtained by liquid chromatography, including liquid chromatography-mass spectrometry (LC-MS), liquid chromatography with ultraviolet or diode-array detection (LC-UV / DAD), evaporative light-scattering detection (LC-ELSD), refractive index detection (LC-RI), or combinations thereof, using appropriate normalization or calibration methods.

[0111] The phrase “digoxin derivative” refers to digoxin, a prodrug therefore and / or an analog thereof. The primary in vivo metabolite of digitoxin is digoxin and / or digitoxigenin, formed via C-12 hydroxylation. For digoxin, dihydrodigoxin and other hydroxylated products are metabolites. Major metabolites include digoxigenin bis-digitoxoside for digoxin or similar derivatives for digitoxin. Examples of digitoxin analogs are disclosed in, for example, ACS Chem Biol. 2015 Feb 20; 10(2):561-9.(Cardiac glycoside activities link Na(+) / K(+) ATPase ion-transport to breast cancer cell migration via correlative SAR. Magpusao et al.); Biochem Pharmacol. 2014 Marl;88(l):23-35. doi: 10.1016 / j.bcp.2013.10.027. Epub 2013 Nov 11 (Monosaccharide digitoxin derivative sensitize human non- small cell lung cancer cells to anoikis through Mcl-1 proteasomal degradation. Pongrakhananon et al.); Exp Hematol Oncol. 2012 Apr 5;1(1):4. doi: 10.1186 / 2162-3619-1-4 (Digitoxin and its analogs as novel cancer therapeutics. Elbaz et al.); ChemMedChem. 2013 Jan;8(l):63-9. doi:10.1002 / cmdc.201200465. Epub 2012 Nov 8. (C37C4'-Stereochemical Effects of Digitoxigenin a-L- / a-D-Glycoside in Cancer Cytotoxicity. Hinds et al.); Toxicol Appl Pharmacol. 2012 Jan 1 ;258( 1):51-60. (Digitoxin and a synthetic monosaccharide analog inhibit cell viability in lung cancer cells. Elbaz); ACS Med Chem Lett. 2011 Apr 14;2(4):259-263 (C5'-Alkyl Substitution Effects on Digitoxigenin a-l-Glycoside Cancer Cytotoxicity. Wang et al.); Planta Med. 2010 Apr;76(6):561-5 (Inhibitory activity of a phytochemically characterized fraction from Streptocaulon juventas on lung cancer in nude mice. Han et al.); J Nat Prod. 2009 Nov;72(ll):1969-74 (Cytotoxic effects of cardiac glycosides in colon cancer cells, alone and in combination with standard chemotherapeutic drugs. Felth); J Exp Ther Oncol. 2006;5(3): 167-81 (Oleandrin-mediated oxidative stress in human melanoma cells. Newman et al.); Eur J Biochem. 1992 Oct 1 ;209(l):281-9 (Leukotriene uptake by hepatocytes and hepatoma cells. Leier); Cancer Chemother Pharmacol. 1986;18(3):270-5 (Effect of oral high-dose progestins on the disposition of antipyrine, digitoxin, and warfarin in patients with advanced breast cancer. Lundgren); Breast Cancer Res Treat. 1986;7 Suppl:S73-6 (Aminoglutethimide as an inducer of microsomal enzymes. Part 1: Pharmacological aspects. Kvinssland); PNAS August 20. 2005, vol 102, no 35 pp!2305-12310 (Enhancing the anticancer properties of cardiac glycosides by neoglycarandomization. Langenhan et al.); J Cell Physiol. 2015 Aug 11. (Autophagy-Induced Apoptosis in Lung Cancer Cells By a Novel Digitoxin Analog. Kulkami et al.); Oncolmmunology 2:2, February 2013 e23082-l to e23082-7 (Cardiac glycosides and cancer therapy. Menger et al.); Bioorganic & Medicinal Chemistry Letters. Vol. 18, Issue 2, 15 January 2008, pages 670-673 (Modifying the glycosidic linkage in digitoxin analogs provides selective cytotoxins. Langenhan et al.).

[0112] Proliferation assay: An MTT assay was used to determine the sensitivity of the various cell lines to the agents. For the MTT assay, cells were seeded at 1 x 103cells / well in 96-well plates and allowed to attach for 24 hr. The medium was replaced with fresh medium containing control or agent. The cells were treated for 96 hr after which the cells were incubated with MTT reagents and the absorbance read at 600 nm. For cell growth assays, the data are expressed as mean 6 standard deviation. Control and treated cells w'ere compared using the Student’s t-test (p < 0.05).

[0113] Calculating the Combination Index. To quantify the interaction between two compounds, a combination index (CI) was calculated using an TC50-shift (doseadditivity) method based on Chou-Talalay principles (Chou and Talalay, Advances in Enzyme Regulation, v. 22, 1984, pp. 27-55; Soriano et al.. Cancer Research 59:6178— 6184, 1999); Planta Medica 72:1200-1206, 2006). In this approach, CI is calculated as:

[0114] CI and its corresponding effects are as follows: >1.3, antagonism; 1.1-1.3, moderate antagonism; 0.9-1.1, additive effect; 0.8-0.9, slight synergism; 0.6-0.8, moderate synergism; <0.6, strong synergism.

[0115] For Actein + sulindac sulfide, synergy was assessed using Bliss independence (Observed / Expected viability ratio) because sulindac sulfide exhibited a non-monotonic dose-response (viability >100% at intermediate doses), which precluded standard median-effect analysis. Under Bliss independence, ABliss score > 0 indicates synergy.

[0116] As used herein, the term "combination" when describing a method of treatment refers to the use of two or more active agents that are administered together or separately as part of a coordinated treatment regimen. Such administration may occur via a physical combination or co-formulation of the active ingredients (e.g., in a single dosage form), or via separate administration, whether simultaneous or sequential, provided that the agents are present concurrently at the site of action for a therapeutically effective period of time.

[0117] In vitro synergy data described herein were generated under conditions in which the active agents were contacted with cells simultaneously, such that both agentswere present concurrently in the culture medium. This experimental design models synergistic interaction when the agents are present together in the therapeutic target environment.

[0118] As used herein, the term “approximately” or “about,” as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In certain embodiments, the term “approximately” or “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%. 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).

[0119] As used herein, the term “patient” or “subject” refers to any organism to which a provided composition may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Typical patients include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, a patient is a human. A human includes pre and post-natal forms.

[0120] Pharmaceutically acceptable: The term “pharmaceutically acceptable” as used herein, refers to substances that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. For example, a composition can include a pharmaceutically acceptable ester or amide of a compound herein. In certain implementations, a composition includes a pharmaceutically acceptable salt of a compound herein. Non-limiting examples of pharmaceutically acceptable salts include carboxylate salts, amino acid addition salts and zwitterionic forms thereof, which are known to those skilled in the art as suitable for use with humans and animals. In cases where a compound is sufficiently basic or acidic to form a stable nontoxic acid or base salt, a composition includes a pharmaceutically acceptable salt of the compound. Nonlimiting examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids that form a physiological acceptable anion, non-limiting examples ofwhich include tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, alpha-ketoglutarate, and alpha-glycerophosphate. Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts. Pharmaceutically acceptable salts are obtained using standard procedures known in the art. For example, pharmaceutically acceptable salts may be obtained by reacting a sufficiently basic compound with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example, calcium, magnesium) salts of carboxylic acids and other anionic groups in molecules within a pharmaceutical composition also are contemplated.

[0121] As used herein, the term “therapeutically effective amount” of a therapeutic agent means an amount that is sufficient, when administered to a subject suffering from or susceptible to a disease, disorder, and / or condition, to treat, diagnose, prevent, and / or delay the onset of the symptom(s) of the disease, disorder, and / or condition. It will be appreciated by those of ordinary skill in the art that a therapeutically effective amount is typically administered via a dosing regimen comprising at least one unit dose.

[0122] Treating: As used herein, the term “treat,” “treatment,” or “treating” refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of and / or reduce incidence of one or more symptoms or features of a particular disease, disorder, and / or condition. Treatment may be administered to a subject who does not exhibit signs of a disease and / or exhibits only early signs of the disease for the purpose of decreasing the risk of developing pathology associated with the disease.

[0123] In some embodiments, the disclosed combinations are used in a method for synergistically inhibiting growth of colon adenocarcinoma cells. In another embodiment, the disclosed combinations of digoxin and simvastatin are used in a method for synergistically inhibiting growth of ER+breast cancer cells.

[0124] In some embodiments, the disclosed combinations have a synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells as determined by Bliss independence analysis with an Observed / Expected viability ratio of less than 1.0 whentested in an in vitro cell viability assay. In another embodiment, the disclosed combinations of digoxin and simvastatin have a synergistic growth inhibition MCF7 (ER+) breast cancer cells as determined by Bliss independence analysis with an Observed / Expected viability ratio of less than 1.0 when tested in an in vitro cell viability assay.

[0125] In some embodiments, the disclosed combinations have a synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells as determined by a AHSA > 0 as determined by comparison to the most effective single agent. In another embodiment, the disclosed combinations of digoxin and simvastatin have a synergistic growth inhibition MCF7 (ER+) breast cancer cells as determined by a AHSA > 0 as determined by comparison to the most effective single agent.

[0126] This written description uses examples to disclose the invention, including the best mode, and also to enable any person skilled in the art to practice the invention, including making and using any devices or systems and performing any incorporated methods. The patentable scope of the invention is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal language of the claims.Al. A method for treating colorectal cancer in a patient, the method comprising: administering to the patient a therapeutically effective amount of a combination of a rosemary extract and a synergistic additive selected from the group consisting of simvastatin, actein and combinations thereof, wherein the combination exhibits a synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.8.A2. The method of claim Al, wherein the cancer is colon cancer.A3. The method of any one of claims A1-A2, wherein the rosemary extract is an acetone extract of rosemary leaves that comprises 48+10 % carnosic acid; 8+5 % 12-O-methyl carnosic acid; 3±2 % carnosol and a remainder that is acid insoluble solids, as determined by liquid chromatography.A4. The method of any one of claims A1-A2, wherein the rosemary extract is an acetone extract of rosemary leaves that comprises 48+5 % carnosic acid; 8±5 % 12-O-methyl carnosic acid; 3±2 % carnosol and a remainder that is acid insoluble solids, as determined by liquid chromatography.A5. The method of any one of claims A1-A2, wherein the rosemary extract is an acetone extract of rosemary leaves that comprises 48+3 % carnosic acid; 8±2 % 12-O-methyl carnosic acid; 3± 1 % carnosol and a remainder that is acid insoluble solids, as determined by liquid chromatography.A6. The method of any one of claims A1-A5, wherein the rosemary extract and the synergistic additive are administered simultaneously.A7. The method of any one of claims A1-A5, wherein the rosemary extract and the synergistic additive are administered sequentially such that the rosemary extract and the synergistic additive are simultaneously present in the patient.A8. The method of any one of claims A1-A7, wherein the combination is administered orally.A9. The method of any one of claims A1-A7, wherein the combination is administered orally, and the combination is formulated as a tablet or a liquid. A 10. The method of any one of claims A1-A7, wherein the combination is administered topically to a portion of the subject.All. The method of any one of claims A1-A7, wherein the combination is administered rectally or by colonic delivery to a portion of the subject.A12. The method of any one of claims A1-A7, wherein the combination is administered topically, and the combination is formulated as a liquid, a foam or a cream.A 13. The method of any one of claims A1-A7, wherein the combination is administered topically, and the combination is formulated as an anal suppository. A 14. The method of any one of claims A1-A7, wherein the combination is administered parenterally.A15. The method of any one of claims A1-A7, wherein the combination is administered intravenously.Bl. The method of any one of claims A1-A15, wherein the synergistic additive is simvastatin.B2. The method of claim Bl, wherein the combination consists essentially of the rosemary extract and the simvastatin such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.7 when tested in an in vitro assay.B3. The method of claim Bl, wherein the combination consists essentially of the rosemary extract and the simvastatin such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.6 when tested in an in vitro assay.B4. The method of claim Bl, wherein the combination consists essentially of the rosemary extract and the simvastatin such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.5 when tested in an in vitro assay.B5. The method of claim Bl, wherein the combination consists essentially of the rosemary extract and the simvastatin such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.4 when tested in an in vitro assay.B6. The method of any one of claims B 1-B5, wherein the rosemary extract and the simvastatin are delivered such that cancer cells are contacted with a rosemary extract concentration of about 30 |iG / mL and a simvastatin concentration of about 10 pg / mL.B7. The method of any one of claims B 1-B5, wherein the rosemary extract and the simvastatin are delivered such that cancer cells are contacted with a rosemary extract concentration of about 10 pg / mL and a simvastatin concentration of about 2 pg / mL.Bl’. A composition of matter comprising:a combination of a rosemary extract and simvastatin.B2’ . The composition of matter of claim Bl’, wherein the combination consists essentially of the rosemary extract and the simvastatin such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.8 when tested in an in vitro assay.B3’. The composition of matter of claim Bl’, wherein the combination consists essentially of the rosemary extract and the simvastatin such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.7 when tested in an in vitro assay.B4’. The composition of matter of claim Bl’, wherein the combination consists essentially of the rosemary extract and the simvastatin such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.6 when tested in an in vitro assay.B5’. The composition of matter of claim Bl’, wherein the combination consists essentially of the rosemary extract and the simvastatin such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53mutant) cells such that the combination has a Combination Index (CI) of less than 0.5 when tested in an in vitro assay.B6’. The composition of matter of claim Bl’, wherein the combination consists essentially of the rosemary extract and the simvastatin such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.4 when tested in an in vitro assay.B7’. The composition of matter of any one of claims B l’-B6’, wherein the composition exhibits a rosemary extract concentration of about 30 pg / mL and a simvastatin concentration of about 10 pg / mL.B8’. The composition of matter of any one of claims Bl’-B6’, wherein the composition exhibits a rosemary extract concentration of about 30 pg / mL and a simvastatin concentration of about 2 pg / mL.B9’. The composition of matter of any one of claims Bl’-B8’, wherein the rosemary extract is an acetone extract of rosemary leaves that comprises 48 + 10 % carnosic acid; 8+5 % 12-O-methyl carnosic acid: 3±2 % carnosol and a remainder that is acid insoluble solids, as determined by liquid chromatography.B10’. The composition of matter of any one of claims Bl’-B8’, wherein the rosemary extract is an acetone extract of rosemary leaves that comprises 48+5 % carnosic acid; 8+5 % 12-O-methyl carnosic acid; 3±2 % carnosol and a remainder that is acid insoluble solids, as determined by liquid chromatography.Bll’. The composition of matter of any one of claims Bl’-B8’, wherein the rosemary extract is an acetone extract of rosemary leaves that comprises 48+3 % carnosic acid; 8±2 % 12-O-methyl carnosic acid; 3±1 % carnosol and a remainder that is acid insoluble solids, as determined by liquid chromatography.B12’. The composition of matter of any one of claims Bl’-Bll’, wherein the combination is formulated as a tablet or a liquid.B 13 ’ . The composition of matter of any one of claims Bl’-Bll’, wherein the combination is formulated as a liquid, a foam or a cream.B 14’ . The composition of matter of any one of claims B 1’ -B 11’ , wherein the combination is formulated as an anal suppository.Cl. The method of any one of claims A1-A15, wherein the synergistic additive is actein.C2. The method of claim Cl, wherein the combination consists essentially of the rosemary extract and the actein such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.7 when tested in an in vitro assay.C3. The method of claim Cl, wherein the combination consists essentially of the rosemary extract and the actein such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.6 when tested in an in vitro assay.C4. The method of claim Cl, wherein the combination consists essentially of the rosemary extract and the actein such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.5 when tested in an in vitro assay.C5. The method of claim Cl, wherein the combination consists essentially of the rosemary extract and the actein such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.4 when tested in an in vitro assay.C6. The method of claim Cl, wherein the combination consists essentially of the rosemary extract and the actein such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such thatthe combination has a Combination Index (CI) of less than 0.3 when tested in an in vitro assay.C7. The method of any one of claims C1-C5, wherein the rosemary extract and the actein are delivered such that cancer cells are contacted with a rosemary concentration of about 20 pg / mL and an actein concentration of about 30 pg / mL. C8. The method of any one of claims C1-C5, wherein the rosemary extract and the actein are delivered such that cancer cells are contacted with a rosemary extract concentration of about 10 pg / mL and an actein concentration of about 2 pg / mL.C 1’ . A composition of matter comprising:a combination of a rosemary extract and actein.C2’. The composition of matter of claim Cl’, wherein the combination consists essentially of the rosemary extract and the actein such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.8 when tested in an in vitro assay.C3’. The composition of matter of claim Cl’, wherein the combination consists essentially of the rosemary extract and the actein such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.7 when tested in an in vitro assay.C4’. The composition of matter of claim Cl’, wherein the combination consists essentially of the rosemary extract and the actein such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.6 when tested in an in vitro assay.C5 ’ . The composition of matter of claim Cl’, wherein the combination consists essentially of the rosemary extract and the actein such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53mutant) cells such that the combination has a Combination Index (CI) of less than 0.5 when tested in an in vitro assay.C6’. The composition of matter of claim Cl’, wherein the combination consists essentially of the rosemary extract and the actein such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.4 when tested in an in vitro assay.C7’. The composition of matter of claim Cl’, wherein the combination consists essentially of the rosemary extract and the actein such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.3 when tested in an in vitro assay.C8’. The composition of matter of any one of claims Cl’-C7’, wherein the composition exhibits a rosemary extract concentration of about 20 pg / mL and an actein concentration of about 30 pg / mL.C9’. The composition of matter of any one of claims Cl’-C7’, wherein the composition exhibits a rosemary extract concentration of about 10 pg / mL and an actein concentration of about 2 pg / mL.CIO’. The composition of matter of any one of claims Cl’-C9’, wherein the combination is formulated as a tablet or a liquid.Cl 1’. The composition of matter of any one of claims Cl’-C9’, wherein the combination is formulated as a liquid, a foam or a cream.C12’. The composition of matter of any one of claims Cl’-C9’, wherein the combination is formulated as an anal suppository.DI. A method for treating colorectal cancer in a patient, the method comprising: administering to the patient a therapeutically effective amount of a combination of actein and a therapeutically effective amount of sulindac sulfide, wherein the combination exhibits a synergistic growth inhibition on HT29 colonadenocarcinoma (TP53 mutant) cells such that the combination has a ABliss score > 0.D2. The method of claim DI, wherein the cancer is colon cancer,D3. The method of any one of claims D1-D2, wherein the actein and the sulindac sulfide are administered simultaneously,D4. The method of any one of claims D1-D2, wherein the actein and the sulindac sulfide are administered sequentially such that the actein and the sulindac sulfide are simultaneously present in the patient.D5. The method of any one of claims D1-D2, wherein the combination is administered orally.D6. The method of any one of claims D1-D2, wherein the combination is administered orally, and the combination is formulated as a tablet or a liquid. D7. The method of any one of claims D1-D2, wherein the combination is administered topically to a portion of the subject.D8. The method of any one of claims D1-D2, wherein the combination is administered rectally or by colonic delivery to a portion of the subject.D9. The method of any one of claims D1-D2, wherein the combination is administered topically, and the combination is formulated as a liquid, a foam or a cream.DIO. The method of any one of claims D1-D2, wherein the combination is administered topically, and the combination is formulated as an anal suppository. Dll. The method of any one of claims D1-D2, wherein the combination is administered parenterally.D12. The method of any one of claims D1-D2, wherein the combination is administered intravenously.D13. The method of any one of claims D1-D12, wherein the combination consists essentially of the actein and the sulindac sulfide such that the combination exhibits a ABliss score > 0 on HT29 colon adenocarcinoma (TP53 mutant) cells.D14. The method of any one of claims D1-D12, wherein the combination consists essentially of the actein and the sulindac sulfide such that the combination exhibits a Bliss ratio (Observed / Expected) < 1.0 on HT29 colon adenocarcinoma (TP53 mutant) cells.D15. The method of any one of claims D1-D14, wherein the actein and the sulindac sulfide are delivered such that cancer cells are contacted with an actein concentration of about 30 pg / mL and a sulindac sulfide concentration of about 25 pg / mL.DI’. A composition of matter comprising:a combination of actein and sulindac sulfide.D2’. The composition of matter of claim DI’, wherein the combination consists essentially of the actein and the sulindac sulfide such that the combination exhibits a ABliss score > 0 on HT29 colon adenocarcinoma (TP53 mutant) cells. D3’. The composition of matter of any one of claims DI -DI 1, wherein the combination consists essentially of the actein and the sulindac sulfide such that the combination exhibits a Bliss ratio (Observed / Expected) < 1.0 on HT29 colon adenocarcinoma (TP53 mutant) cells.D4’. The composition of matter of claim DI’, wherein the composition exhibits an actein concentration of about 30 pg / mL and a sulindac sulfide concentration of about 25 pg / mL.D5’. The composition of matter of any one of claims Dl’-D4’, wherein the combination is formulated as a tablet or a liquid.D6’. The composition of matter of any one of claims Dl’-D4’, wherein the combination is formulated as a liquid, a foam or a cream.D7’. The composition of matter of any one of claims Dl’-D4’, wherein the combination is formulated as an anal suppository.El. A method for treating cancer in a patient, the method comprisingadministering to the patient a therapeutically effective amount of a combination of a kava extract and a therapeutically effective amount of a synergistic additive selected from the group consisting of simvastatin, 5 -fluorouracil (5-FU). a turmeric extract and combinations thereof, wherein the combination exhibits a synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.8. E2. The method of claim El, wherein the cancer is colon cancer.E3. The method of any one of claims E1-E2, wherein the kava extract is about 11-25 % dihydromethysticin, about 50-74 % 7,8-dihydrokavain, 6-10 % kavain, about 5- 10 % 5,6,7,8-tetrahydroyangonin, about 0.1-0.5 % 11 -hydroxy- 12- methoxydihydrokavain, about 0.1-1.0 % prenyl caffeate. about 0-1.0 wt% pinostrobin chaicone, about 0.1-3.0 % 11-methoxytetrahydroyangonin, about 0.1- 1.0 % awaine, about 0.5-2.0 % methysticin, about 0.5-2.0 % yangonin, about 0.5- 5.0 % desmethoxyyangonin, and about 0.1-1.0 wt% flavokawain B as determined by liquid chromatography.E4. The method of any one of claims E1-E3, wherein the kava extract and the synergistic additive are administered simultaneously.E5. The method of any one of claims El- E3, wherein the kava extract and the synergistic additive are administered sequentially such that the kava extract and the synergistic additive are simultaneously present in the patient.E6. The method of any one of claims E1-E3, wherein the combination is administered orally.E7. The method of any one of claims E1-E3, wherein the combination is administered orally, and the combination is formulated as a tablet or a liquid.E8. The method of any one of claims E1-E3, wherein the combination is administered topically to a portion of the subject.E9. The method of any one of claims E1-E3, wherein the combination is administered rectally or by colonic delivery to a portion of the subject.E10. The method of any one of claims E1-E3, wherein the combination is administered topically, and the combination is formulated as a liquid, a foam or a cream. Ell. The method of any one of claims E1-E3, wherein the combination is administered topically, and the combination is formulated as an anal suppository.El 2. The method of any one of claims E1-E3, wherein the combination is administered parenterally.Fl . The method of any one of claims El -El 2, wherein the synergistic additive is simvastatin.F2. The method of claim Fl, wherein the combination consists essentially of the kava extract and the simvastatin such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.7 when tested in an in vitro assay.F3. The method of claim Fl, wherein the combination consists essentially of the kava extract and the simvastatin such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.6 when tested in an in vitro assay.F4. The method of claim Fl, wherein the combination consists essentially of the kava extract and the simvastatin such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.5 when tested in an in vitro assay.F5. The method of claim Fl, wherein the combination consists essentially of the kava extract and the simvastatin such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that thecombination has a Combination Index (CI) of less than 0.4 when tested in an in vitro assay.F6. The method of claim Fl, wherein the combination consists essentially of the kava extract and the simvastatin such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.3 when tested in an in vitro assay.F7. The method of any one of claims F1-F6. wherein the kava extract and the simvastatin are delivered such that cancer cells are contacted with a kava extract concentration of about 2 pg / mL and a simvastatin concentration of about 2 Fg / mL.Fl’ . A composition of matter comprising:a combination of a kava extract and simvastatin.F2’. The composition of matter of claim Fl’, wherein the combination consists essentially of the kava extract and the simvastatin such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.8 when tested in an in vitro assay.F3’. The composition of matter of claim Fl’, wherein the combination consists essentially of the kava extract and the simvastatin such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.7 when tested in an in vitro assay.F4’. The composition of matter of claim Fl’, wherein the combination consists essentially of the kava extract and the simvastatin such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.6 when tested in an in vitro assay.F5 ’ . The composition of matter of claim Fl ’ , wherein the combination consists essentially of the kava extract and the simvastatin such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.5 when tested in an in vitro assay.F6’. The composition of matter of claim Fl’, wherein the combination consists essentially of the kava extract and the simvastatin such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.4 when tested in an in vitro assay.F7’. The composition of matter of claim Fl’, wherein the combination consists essentially of the kava extract and the simvastatin such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.3 when tested in an in vitro assay.F8’. The composition of matter of any one of claims Fl’-F7’, wherein the composition exhibits a kava extract concentration of about 2 pg / mL and a simvastatin concentration of about 2 pg / mL.F9’. The composition of matter of any one of claims Fl’-F8’. wherein the combination is formulated as a tablet or a liquid.Fl O’. The composition of matter of any one of claims Fl’-F8’, wherein the combination is formulated as a liquid, a foam or a cream.FIT. The composition of matter of any one of claims Fl’-F8’, wherein the combination is formulated as an anal suppository.F12’. The composition of matter of any one of claims Fl’-Fl 1’, wherein the kava extract is about 11-25 % dihydromethysticin, about 50-74 % 7,8-dihydrokavain, about 6-10 % kavain, about 5-10 % 5,6,7,8-tetrahydroyangonin, about 0.1-0.5 % 11 -hydroxy- 12-methoxydihydrokavain, about 0.1- 1.0 % prenyl caffeate, about 0- 1.0 % pinostrobin chaicone, about 0.1-3.0 % 11-methoxytetrahydroyangonin,about 0.1-1.0 % awaine, about 0.5-2.0 % methysticin, about 0.5-2.0 % yangonin, about 0.5-5.0 % desmethoxyyangonin, and about 0.1- 1.0 % flavokawain B as determined by liquid chromatography.Gl. The method of any one of claims El-Ell, wherein the synergistic additive is 5- fluorouracil (5-FU).G2. The method of claim Gl, wherein the combination consists essentially of the kava extract and the 5-fluorouracil (5-FU) such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.7 when tested in an in vitro assay.G3. The method of claim Gl, wherein the combination consists essentially of the kava extract and the 5-fluorouracil (5-FU) such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.6 when tested in an in vitro assay.G4. The method of claim Gl, wherein the combination consists essentially of the kava extract and the 5-fluorouracil (5-FU) such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.5 when tested in an in vitro assay.G5. The method of claim Gl, wherein the combination consists essentially of the kava extract and the 5-fluorouracil (5-FU) such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.4 when tested in an in vitro assay.G6. The method of claim Gl, wherein the combination consists essentially of the kava extract and the 5-fluorouracil (5-FU) such that the combination exhibitssynergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.3 when tested in an in vitro assay.G7. The method of any one of claims G1-G6, wherein the kava extract and the 5- fluorouracil (5-FU) are delivered such that cancer cells are contacted with a kava extract concentration of about 30 pg / mL and a 5 -fluorouracil (5-FU) concentration of about 2 |ig / mL.G8. The method of any one of claims G1-G6, wherein the kava extract and the 5- fluorouracil (5-FU) are delivered such that cancer cells are contacted with a kava extract concentration of about 0.8 |ig / mL and a 5 -fluorouracil (5-FU) concentration of about 2 pg / mL.G 1 ’ . A composition of matter comprising:a combination of a kava extract and 5 -fluorouracil (5-FU).G2’. The composition of matter of claim GU, wherein the combination consists essentially of the kava extract and the 5 -fluorouracil (5-FU) such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (Cl) of less than 0.8 when tested in an in vitro assay.G3’. The composition of matter of claim GU, wherein the combination consists essentially of the kava extract and the 5 -fluorouracil (5-FU) such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.7 when tested in an in vitro assay.G4’. The composition of matter of claim GU, wherein the combination consists essentially of the kava extract and the 5 -fluorouracil (5-FU) such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.6 when tested in an in vitro assay.G5’. The composition of matter of claim GT, wherein the combination consists essentially of the kava extract and the 5 -fluorouracil (5-FU) such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.5 when tested in an in vitro assay.G6’. The composition of matter of claim Gl’, wherein the combination consists essentially of the kava extract and the 5 -fluorouracil (5-FU) such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.4 when tested in an in vitro assay.G7’. The composition of matter of any one of claims GU-G7’, wherein the composition exhibits a kava extract concentration of about 30 pg / mL and a 5- fluorouracil (5-FU) concentration of about 2 pg / mL.G8’. The composition of matter of any one of claims GU-G7’, wherein the composition exhibits a kava extract concentration of about 0.8 pg / mL and a 5- fluorouracil (5-FU) concentration of about 2 pg / mL.G9’. The composition of matter of any one of claims GU-G8’, wherein the combination is formulated as a tablet or a liquid.GIO’. The composition of matter of any one of claims Gl’-G8’, wherein the combination is formulated as a liquid, a foam or a cream.G 11 ’ . The composition of matter of any one of claims G 1 ’ -G8 ’ , wherein the combination is formulated as an anal suppository.G12’. The composition of matter of any one of claims Gl’-Gl 1, wherein the kava extract is about 11-25 % dihydromethysticin, about 50-74 % 7,8-dihydrokavain, about 6-10 % kavain, about 5-10 % 5,6,7,8-tetrahydroyangonin, about 0.1-0.5 % 11 -hydroxy- 12-methoxy dihydrokavain, about 0.1-1.0 % prenyl caffeate, about 0- 1.0 % pinostrobin chaicone, about 0.1-3.0 % 11-methoxytetrahydroyangonin, about 0.1- 1.0 % awaine, about 0.5-2.0 % methysticin, about 0.5-2.0 % yangonin,about 0.5-5.0 % desmethoxyyangonin, and about 0.1 -1.0 % flavokawain B as determined by liquid chromatography.Hl. The method of any one of claims El -El 1, wherein the synergistic additive is a turmeric extract.H2. The method of claim Hl, wherein the combination consists essentially of the kava extract and the turmeric extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.7 when tested in an in vitro assay.H3. The method of claim Hl, wherein the combination consists essentially of the kava extract and the turmeric extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.6 when tested in an in vitro assay.H4. The method of claim Hl, wherein the combination consists essentially of the kava extract and the turmeric extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.5 when tested in an in vitro assay.H5. The method of any one of claims H1-H4, wherein the kava extract and the turmeric extract are delivered such that cancer cells are contacted with a kava extract concentration of about 2 |ig / mL and a turmeric extract concentration of about 2 |ig / mL.H6. The method of any one of claims H1-H4, wherein the kava extract and the turmeric extract are delivered such that cancer cells are contacted with a kava extract concentration of about 0.8 pg / mL and a turmeric extract concentration of about 2 |ig / mL.H7. The method of any one of claims H1-H6, wherein the turmeric extract is at least 95 wt% curcuminoids selected from the group consisting of curcumin, desmethoxycurcumin, bis-demethoxycurcumin and combinations thereof.H8. The method of any one of claims H1-H7, wherein the combination is free of epigallocatechin-3-gallate (EGCG).H9. The method of any one of claims H1-H7, wherein the combination is free of resveratrol.H10. The method of any one of claims H1-H7, wherein the combination is free of both epigallocatechin-3-gallate (EGCG) and resveratrol.Hl ’ A composition of matter comprising:a combination of a kava extract and a turmeric extract.H2’. The composition of matter of claim Hl’, wherein the combination consists essentially of the kava extract and the turmeric extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.8 when tested in an in vitro assay.H3’. The composition of matter of claim Hl’, wherein the combination consists essentially of the kava extract and the turmeric extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.7 when tested in an in vitro assay.H4’. The composition of matter of claim Hl’, wherein the combination consists essentially of the kava extract and the turmeric extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.6 when tested in an in vitro assay.H5 ’ . The composition of matter of claim Hl’, wherein the combination consists essentially of the kava extract and the turmeric extract such that the combinationexhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.5 when tested in an in vitro assay..H6’. The composition of matter of claim Hl’, wherein the composition exhibits a kava extract concentration of about 2 pg / mL and a turmeric extract concentration of about 2 pg / mL.H7’. The composition of matter of claim Hl’, wherein the composition exhibits a kava extract concentration of about 0.8 pg / mL and a turmeric extract concentration of about 2 pg / mL.H8’. The composition of matter of any one of claims Hl’-H7’, wherein the combination is formulated as a tablet or a liquid.H9’. The composition of matter of any one of claims Hl’-H7’, wherein the combination is formulated as a liquid, a foam or a cream.H10’. The composition of matter of any one of claims Hl’-H7’, wherein the combination is formulated as an anal suppository.Hl 1’. The composition of matter of any one of claims Hl’-H10’, wherein the kava extract is about 11-25 % dihydromethysticin, 50-74 % 7,8-dihydrokavain, 6-10 % kavain, 5-10 % 5,6,7,8-tetrahydroyangonin, 0.1-0.5 % 11 -hydroxy- 12- methoxydihydrokavain, 0.1-1.0 % prenyl caffeate, 0-1.0 % pinostrobin chaicone, 0.1-3.0 % 11-methoxytetrahydroyangonin, 0.1-1.0 % awaine, 0.5-2.0 % methysticin, 0.5-2.0 % yangonin, 0.5-5.0 % desmethoxyyangonin, and 0.1-1.0 % flavokawain B as determined by liquid chromatography.Hl 2. The composition of matter of any one of claims Hl ’-Hl 1’, wherein the turmeric extract is at least 95 wt% curcuminoids selected from the group consisting of curcumin, desmethoxycurcumin, bis-demethoxycurcumin and combinations thereof.11. A method for treating cancer in a patient, the method comprising:administering to the patient a therapeutically effective amount of a combination of a kava extract and a therapeutically effective amount of a ginger extract, wherein the combination exhibits a synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.8.The method of claim II, wherein the cancer is colon cancer.The method of any one of claims 11-12, wherein the kava extract and the ginger extract are administered simultaneously.The method of any one of claims 11 -12, wherein the kava extract and the ginger extract are administered sequentially such that the kava extract and the ginger extract are simultaneously present in the patient.The method of any one of claims 11-12, wherein the combination is administered orally.The method of any one of claims 11-12, wherein the combination is administered orally, and the combination is formulated as a tablet or a liquid.The method of any one of claims 11-12, wherein the combination is administered topically to a portion of the subject.The method of any one of claims 11-12, wherein the combination is administered rectally or by colonic delivery to a portion of the subject.The method of any one of claims 11-12, wherein the combination is administered topically, and the combination is formulated as a liquid, a foam or a cream.The method of any one of claims 11-12, wherein the combination is administered topically, and the combination is formulated as an anal suppository.The method of any one of claims 11-12, wherein the combination is administered parenterally.The method of any one of claims Il-Ill, wherein the combination consists essentially of the kava extract and the ginger extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53mutant) cells such that the combination has a Combination Index (CI) of less than 0.7 when tested in an in vitro assay.The method of any one of claims II -Il 1, wherein the combination consists essentially of the kava extract and the ginger extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.6 when tested in an in vitro assay.The method of any one of claims II -Il 1, wherein the combination consists essentially of the kava extract and the ginger extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.5 when tested in an in vitro assay.The method of any one of claims 11-114, wherein the kava extract and the ginger extract are delivered such that cancer cells are contacted with a kava extract concentration of about 2 |ig / mL and a ginger extract concentration of about 2 Pg / mL.The method of any one of claims 11-114, wherein the kava extract and the ginger extract are delivered such that cancer cells are contacted with a kava extract concentration of about 0.8 pg / mL and a ginger extract concentration of about 10 Pg / mL.The method of any one of claims 11-116, wherein the kava extract comprises about 40-45 wt% dihydrokavain, about 15-20 wt% kavain, about 15-20 wt% dihydromethysticin, >0 but < about 5 wt% methysticin, about 5-10 wt% yangonin and 3-5 wt% demethoxyyangonin.The method of any one of claims 11-117, wherein the ginger extract is greater than about 20 wt% gingerols and shogaols, about 8-10 wt% 6-gingerol, about 2-3 wt% 8-gingerol. about 3-4 wt% 10-gingerol, about 2-3 wt% shogaols with the remainder being ginger polysaccharides, proteins, and native non-volatile components.’ A composition of matter comprising:a combination of a kava extract and a ginger extract.’. The composition of matter of claim II’, wherein the combination consists essentially of the kava extract and the ginger extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.8 when tested in an in vitro assay.’. The composition of matter of claim 11’, wherein the combination consists essentially of the kava extract and the ginger extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.7 when tested in an in vitro assay.’. The composition of matter of claim 11’, wherein the combination consists essentially of the kava extract and the ginger extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.6 when tested in an in vitro assay.’. The composition of matter of claim 11’, wherein the combination consists essentially of the kava extract and the ginger extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.5 when tested in an in vitro assay.’. The composition of matter of any one of claims II ’-15’ wherein the composition exhibits a kava extract concentration of about 2 pg / mL and a ginger extract concentration of about 10 pg / mL.’. The composition of matter of any one of claims II ’-15’ wherein the composition exhibits a kava extract concentration of about 0.8 pg / mL and a ginger extract concentration of about 10 pg / mL.18’. The composition of matter of any one of claims II ’-17’, wherein the combination is formulated as a tablet or a liquid.19’. The composition of matter of any one of claims II ’-17’, wherein the combination is formulated as a liquid, a foam or a cream.110’. The composition of matter of any one of claims II ’-17’, wherein the combination is formulated as an anal suppository.Ill’. The composition of matter of any one of claims II ’-110’, wherein the kava extract comprises 40-45 wt% dihydrokavain, 15-20 wt% kavain, 15-20 wt% dihydromethysticin, >0 but < 5 wt% methysticin, 5-10 wt% yangonin and 3-5 wt% demethoxyyangonin.112’. The composition of matter of any one of claims II ’-Il 1’. wherein the ginger extract is greater than about 20 wt% gingerols and shogaols, about 8-10 wt% 6- gingerol, about 2-3 wt% 8-gingerol, about 3-4 wt% 10-gingerol, about 2-3 wt% shogaols with the remainder being ginger polysaccharides, proteins, and native non-volatile components.JI . A method for treating cancer in a patient, the method comprising administering to the patient a therapeutically effective amount of a combination of dihydroxymethysticin (DHM) and a therapeutically effective amount of a synergistic additive selected from the group consisting of a turmeric extract, 5 -fluorouracil (5-FU), a hibiscus extract and combinations thereof, wherein the combination exhibits a synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.8.J2. The method of claim J 1 , wherein the cancer is colon cancer.J3. The method of any one of claims J1-J2, wherein the dihydroxymethysticin (DHM) and the synergistic additive are administered simultaneously.J4. The method of any one of claims J1-J2, wherein the dihydroxymethysticin (DHM) and the synergistic additive are administered sequentially such that thedihydroxymethysticin (DHM) and the synergistic additive are simultaneously present in the patient.J5. The method of any one of claims J1-J2, wherein the combination is administered orally.J6. The method of any one of claims J1-J2, wherein the combination is administered orally, and the combination is formulated as a tablet or a liquid.J7. The method of any one of claims J1-J2, wherein the combination is administered topically to a portion of the subject.J8. The method of any one of claims 11-12, wherein the combination is administered rectally or by colonic delivery to a portion of the subject.J9. The method of any one of claims J1-J2, wherein the combination is administered topically, and the combination is formulated as a liquid, a foam or a cream. J 10. The method of any one of claims J1-J2, wherein the combination is administered topically, and the combination is formulated as an anal suppository.JI 1. The method of any one of claims J1-J2, wherein the combination is administered parenterally.KI. The method of any one of claims JI -JI 1, wherein the synergistic additive is a turmeric extract.K2. The method of claim KI, wherein the combination consists essentially of the dihydroxymethysticin (DHM) and the turmeric extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.7 when tested in an in vitro assay.K3. The method of claim KI, wherein the combination consists essentially of the dihydroxymethysticin (DHM) and the turmeric extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.6 when tested in an in vitro assay.K4. The method of any one of claims K1-K3, wherein the dihydroxymethysticin (DHM) and the turmeric extract are delivered such that cancer cells are contacted with a dihydroxymethysticin (DHM) concentration of about 2 pg / mL and a turmeric extract concentration of about 3 |ig / mL.K5. The method of any one of claims K1-K4, wherein the turmeric extract is at least 95 wt% curcuminoids selected from the group consisting of curcumin, desmethoxycurcumin, bis-demethoxycurcumin and combinations thereof.K6. The method of any one of claims K1-K5, wherein the combination is free of epigallocatechin-3-gallate (EGCG).K7. The method of any one of claims K1-K5, wherein the combination is free of resveratrol.K8. The method of any one of claims K1-K5, wherein the combination is free of both epigallocatechin-3-gallate (EGCG) and resveratrol.KI ’ A composition of matter comprising:a combination of dihydroxymethysticin (DHM) and a turmeric extract.K2’. The composition of matter of claim KI’, wherein the combination consists essentially of the dihydroxymethysticin (DHM) and the turmeric extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.8 when tested in an in vitro assay.K3’ . The composition of matter of claim KI ’ , wherein the combination consists essentially of the dihydroxymethysticin (DHM) and the turmeric extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.7 when tested in an in vitro assay.K4’ . The composition of matter of claim KI ’ , wherein the combination consists essentially of the dihydroxymethysticin (DHM) and the turmeric extract such that the combination exhibits synergistic growth inhibition on HT29 colonadenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.6 when tested in an in vitro assay.K5 ’ . The composition of matter of claim KI’ , wherein the composition exhibits a dihydroxymethysticin (DHM) concentration of about 2 pg / mL and a turmeric extract concentration of about 3 pg / mL.K6’. The composition of matter of any one of claims Kl’-K5’, wherein the combination is formulated as a tablet or a liquid.K7’. The composition of matter of any one of claims Kl’-K5’, wherein the combination is formulated as a liquid, a foam or a cream.K8’. The composition of matter of any one of claims Kl’-K5’, wherein the combination is formulated as an anal suppository.K9’. The composition of matter of any one of claims Kl’-K8’, wherein the turmeric extract is at least 95 wt% curcuminoids selected from the group consisting of curcumin, desmethoxycurcumin, bis-demethoxycurcumin and combinations thereof.K10’. The composition of matter of any one of claims Kl’-K9’, wherein the combination is free of epigallocatechin-3-gallate (EGCG).KI 1’. The composition of matter of any one of claims Kl’-K9’, wherein the combination is free of resveratrol.K12’. The composition of matter of any one of claims Kl’-K9’, wherein the combination is free of both epigallocatechin-3-gallate (EGCG) and resveratrol.LI. The method of any one of claims J1-J10, wherein the synergistic additive is 5- fluorouracil (5-FU).L2. The method of claim LI, wherein the combination consists essentially of the dihydroxymethysticin (DHM) and the 5-fluorouracil (5-FU) such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.7 when tested in an in vitro assay.L3. The method of claim LI, wherein the combination consists essentially of the dihydroxymethysticin (DHM) and the 5-fluorouracil (5-FU) such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.6 when tested in an in vitro assay.L4. The method of claim LI, wherein the combination consists essentially of the dihydroxymethysticin (DHM) and the 5-fluorouracil (5-FU) such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.5 when tested in an in vitro assay.L5. The method of claim LI, wherein the combination consists essentially of the dihydroxymethysticin (DHM) and the 5-fluorouracil (5-FU) such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.4 when tested in an in vitro assay.L6. The method of any one of claims L1-L5, wherein the dihydroxymethysticin (DHM) and the 5-fluorouracil (5-FU) are delivered such that cancer cells are contacted with a dihydroxymethysticin (DHM) concentration of about 10 |ig / mL and a 5-fluorouracil (5-FU) concentration of about 0.02 pg / mL.L7. The method of any one of claims L1-L5, wherein the dihydroxymethysticin (DHM) and the 5-fluorouracil (5-FU) are delivered such that cancer cells are contacted with a dihydroxymethysticin (DHM) concentration of about 2 pg / mL and a 5-fluorouracil (5-FU) concentration of about 0.2 pg / mL.LU A composition of matter comprising:a combination of dihydroxymethysticin (DHM) and 5-fluorouracil (5-FU). L2’ . The composition of matter of claim LI ’ , wherein the combination consists essentially of the dihydroxymethysticin (DHM) and the 5-fluorouracil (5-FU) such that the combination exhibits synergistic growth inhibition on HT29 colonadenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.8 when tested in an in vitro assay.L3’. The composition of matter of claim LI’, wherein the combination consists essentially of the dihydroxymethysticin (DHM) and the 5 -fluorouracil (5-FU) such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.7 when tested in an in vitro assay.L4’. The composition of matter of claim LI’, wherein the combination consists essentially of the dihydroxymethysticin (DHM) and the 5 -fluorouracil (5-FU) such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.6 when tested in an in vitro assay.L5 ’ . The composition of matter of claim LI ’ , wherein the combination consists essentially of the dihydroxymethysticin (DHM) and the 5 -fluorouracil (5-FU) such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.5 when tested in an in vitro assay.L6’ . The composition of matter of claim LI ’ , wherein the combination consists essentially of the dihydroxymethysticin (DHM) and the 5 -fluorouracil (5-FU) such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.4 when tested in an in vitro assay.L7’. The composition of matter of any one of claims Ll’-L6’, wherein the composition exhibits a dihydroxymethysticin (DHM) concentration of about 10 pg / mL and a 5 -fluorouracil (5-FU) concentration of about 0.02 pg / mL.L8’. The composition of matter of any one of claims Ll’-L6’, wherein the composition exhibits a dihydroxymethysticin (DHM) concentration of about 2 pg / mL and a 5- fluorouracil (5-FU) concentration of about 0.2 pg / mL.L9’. The composition of matter of any one of claims Ll’-L8’, wherein the combination is formulated as a tablet or a liquid.LIO’. The composition of matter of any one of claims Ll’-L8’, wherein the combination is formulated as a liquid, a foam or a cream.LI 1’. The composition of matter of any one of claims Ll’-L8’, wherein the combination is formulated as an anal suppository.Ml. The method of any one of claims JI -J 10, wherein the synergistic additive is a hibiscus extract.M2. The method of claim Ml, wherein the combination consists essentially of the dihydroxymethysticin (DHM) and the hibiscus extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.7 when tested in an in vitro assay.M3. The method of claim Ml, wherein the combination consists essentially of the dihydroxymethysticin (DHM) and the hibiscus extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.6 when tested in an in vitro assay.M4. The method of claim Ml, wherein the combination consists essentially of the dihydroxymethysticin (DHM) and the hibiscus extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.5 when tested in an in vitro assay.M5. The method of claim Ml, wherein the combination consists essentially of the dihydroxymethysticin (DHM) and the hibiscus extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.4 when tested in an in vitro assay.M6. The method of any one of claims M1-M5, wherein the dihydroxymethysticin (DHM) and the hibiscus extract are delivered such that cancer cells are contacted with a dihydroxymethysticin (DHM) concentration of about 2 pg / mL and a hibiscus extract concentration of about 10 |ig / mL.Ml’. A composition of matter comprising:a combination of dihydroxymethysticin (DHM) and hibiscus extract.M2’. The composition of matter of claim Ml’, wherein the combination consists essentially of the dihydroxymethysticin (DHM) and the hibiscus extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.8 when tested in an in vitro assay.M3’. The composition of matter of claim Ml’, wherein the combination consists essentially of the dihydroxymethysticin (DHM) and the hibiscus extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.7 when tested in an in vitro assay.M4’. The composition of matter of claim Ml’, wherein the combination consists essentially of the dihydroxymethysticin (DHM) and the hibiscus extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (Cl) of less than 0.6 when tested in an in vitro assay.M5’. The composition of matter of claim Ml’, wherein the combination consists essentially of the dihydroxymethysticin (DHM) and the hibiscus extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.5 when tested in an in vitro assay.M6’. The composition of matter of claim Ml’, wherein the combination consists essentially of the dihydroxymethysticin (DHM) and the hibiscus extract such thatthe combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.4 when tested in an in vitro assay.M7’. The composition of matter of any one of claims Ml’-M6’, wherein the composition exhibits a dihydroxymethysticin (DHM) concentration of about 2 pg / mL and a hibiscus extract concentration of about 10 pg / mL.M8’. The composition of matter of any one of claims Ml’-M7’, wherein the combination is formulated as a tablet or a liquid.M9’. The composition of matter of any one of claims Ml’-M7’, wherein the combination is formulated as a liquid, a foam or a cream.MIO’. The composition of matter of any one of claims Ml’-M7’. wherein the combination is formulated as an anal suppository.Nl. A method for treating cancer in a patient, the method comprising administering to the patient a therapeutically effective amount of a combination of digoxin or a digoxin derivative and a therapeutically effective amount of a synergistic additive selected from the group consisting of simvastatin, a rosemary extract, a turmeric extract, a kava extract, 5 -fluorouracil (5-FU), a ginger extract and combinations thereof, wherein the combination exhibits a synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.8. N2. The method of claim Nl, wherein the cancer is colon cancer.N3. The method of any one of claims N1-N2, wherein the digoxin or the digoxin derivative and the synergistic additive are administered simultaneously.N4. The method of any one of claims N1-N2, wherein the digoxin or the digoxin derivative and the synergistic additive are administered sequentially such that the digoxin or the digoxin derivative and the synergistic additive are simultaneously present in the patient.N5. The method of any one of claims N1-N2, wherein the combination is administered orally.N6. The method of any one of claims N1-N2, wherein the combination is administered orally, and the combination is formulated as a tablet or a liquid. N7. The method of any one of claims N 1-N2, wherein the combination is administered topically to a portion of the subject.N8. The method of any one of claims N1-N2, wherein the combination is administered rectally or by colonic delivery to a portion of the subject.N9. The method of any one of claims N 1 -N2, wherein the combination is administered topically, and the combination is formulated as a liquid, a foam or a cream.N10. The method of any one of claims N1-N2, wherein the combination is administered topically, and the combination is formulated as an anal suppository. Nil. The method of any one of claims N1-N2, wherein the combination is administered parenterally.0 1. The method of any one of claims N 1 -N 11 , wherein the synergistic additive is simvastatin.02. The method of claim 01, wherein the combination consists essentially of the digoxin or the digoxin derivative and the simvastatin such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.7 when tested in an in vitro assay.03. The method of claim 01, wherein the combination consists essentially of the digoxin or the digoxin derivative and the simvastatin such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.6 when tested in an in vitro assay.. The method of claim 01, wherein the combination consists essentially of the digoxin or the digoxin derivative and the simvastatin such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.5 when tested in an in vitro assay.. The method of claim 01, wherein the combination consists essentially of the digoxin or the digoxin derivative and the simvastatin such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.4 when tested in an in vitro assay.. The method of claim 01, wherein the combination consists essentially of the digoxin or the digoxin derivative and the simvastatin such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.3 when tested in an in vitro assay.. The method of any one of claims 01-06, wherein the digoxin or the digoxin derivative extract and the simvastatin are delivered such that cancer cells are contacted with a digoxin or a digoxin derivative concentration of about 0.04 |ig / mL and a simvastatin concentration of about 10 pg / mL.’ A composition of matter comprising:a combination of digoxin or a digoxin derivative and simvastatin.’. The composition of matter of claim 01’, wherein the combination consists essentially of the digoxin or the digoxin derivative and the simvastatin such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.7 when tested in an in vitro assay.’. The composition of matter of claim 01’, wherein the combination consists essentially of the digoxin or the digoxin derivative and the simvastatin such thatthe combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.6 when tested in an in vitro assay.04’. The composition of matter of claim 01’, wherein the combination consists essentially of the digoxin or the digoxin derivative and the simvastatin such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.5 when tested in an in vitro assay.05’. The composition of matter of any one of claims Ol’-O4’, wherein the composition exhibits a digoxin or the digoxin derivative concentration of about 0.04 pg / mL and a simvastatin concentration of about 10 pg / mL.06’. The composition of matter of any one of claims Ol’-O4’, wherein the combination is formulated as a tablet or a liquid.07’. The composition of matter of any one of claims 01’ -04’, wherein the combination is formulated as a liquid, a foam or a cream.08’. The composition of matter of any one of claims 01’ -04’, wherein the combination is formulated as an anal suppository.Pl. The method of any one of claims Nl-Nl 1, wherein the synergistic additive is a rosemary extract.P2. The method of claim Pl, wherein the rosemary extract is an acetone extract of rosemary leaves that comprises 48±10 % camosic acid; 8±5 % 12-0-methyl carnosic acid; 3±2 % camosol and a remainder that is acid insoluble solids, as determined by liquid chromatography.P3. The method of claim Pl, wherein the rosemary extract is an acetone extract of rosemary leaves that comprises 48±5 % camosic acid; 8±5 % 12-0-methyl camosic acid; 3 ±2 % camosol and a remainder that is acid insoluble solids, as determined by liquid chromatography.P4. The method of claim Pl, wherein the rosemary extract is an acetone extract of rosemary leaves that comprises 48±3 % camosic acid; 8±2 % 12-O-methyl camosic acid; 3±1 % camosol and a remainder that is acid insoluble solids, as determined by liquid chromatography.P5. The method of any one of claims P1-P4, wherein the combination consists essentially of the digoxin or the digoxin derivative and the rosemary extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.7 when tested in an in vitro assay.P6. The method of any one of claims P1-P4, wherein the combination consists essentially of the digoxin or the digoxin derivative and the rosemary extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.6 when tested in an in vitro assay.P7. The method of any one of claims P1-P4, wherein the combination consists essentially of the digoxin or the digoxin derivative and the rosemary extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.5 when tested in an in vitro assay.P8. The method of any one of claims P1-P7, wherein the digoxin or a digoxin derivative extract and the rosemary extract are delivered such that cancer cells are contacted with a digoxin or a digoxin derivative concentration of about 0.02 pg / mL and a rosemary extract concentration of about 10 pg / mL.Pl’. A composition of matter comprising:a combination of digoxin or a digoxin derivative and a rosemary extract.P2’. The composition of matter of claim Pl’, wherein the combination consists essentially of the digoxin or the digoxin derivative and the rosemary extract such that the combination exhibits synergistic growth inhibition on HT29 colonadenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.7 when tested in an in vitro assay.P3’ . The composition of matter of claim Pl’ , wherein the combination consists essentially of the digoxin or the digoxin derivative and the rosemary extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.6 when tested in an in vitro assay.P4’. The composition of matter of claim Pl’, wherein the combination consists essentially of the digoxin or the digoxin derivative and the rosemary extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.5 when tested in an in vitro assay.P5’. The composition of matter of any one of claims Pl’-P4’, wherein the composition exhibits a digoxin or the digoxin derivative concentration of about 0.02 pg / mL and a rosemary extract concentration of about 10 pg / mL.P6’. The composition of matter of any one of claims Pl’-P5’. wherein the combination is formulated as a tablet or a liquid.P7’. The composition of matter of any one of claims Pl’-P5’, wherein the combination is formulated as a liquid, a foam or a cream.P8’. The composition of matter of any one of claims Pl’-P5’, wherein the combination is formulated as an anal suppository.P9’. The composition of matter of any one of claims Pl’-P8’, wherein the rosemary extract is an acetone extract of rosemary leaves that comprises 48 + 10 % carnosic acid; 8+5 % 12-O-methyl carnosic acid: 3±2 % carnosol and a remainder that is acid insoluble solids, as determined by liquid chromatography.P10’. The composition of matter of any one of claims Pl’-P8’, wherein the rosemary extract is an acetone extract of rosemary leaves that comprises 48+5 % carnosic acid; 8+5 % 12-O-methyl carnosic acid; 3±2 % carnosol and a remainder that is acid insoluble solids, as determined by liquid chromatography.PH’. The composition of matter of any one of claims Pl’-P8’, wherein the rosemary extract is an acetone extract of rosemary leaves that comprises 48 ±3 % camosic acid; 8±2 % 12-O-methyl carnosic acid; 3±1 % carnosol and a remainder that is acid insoluble solids, as determined by liquid chromatography.QI. The method of any one of claims Nl-Nll, wherein the synergistic additive is a turmeric extract.Q2. The method of claim QI, wherein the combination consists essentially of the digoxin or a digoxin and the turmeric extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.7 when tested in an in vitro assay.Q3. The method of claim QI, wherein the combination consists essentially of the digoxin or a digoxin and the turmeric extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.6 when tested in an in vitro assay.Q4. The method of claim QI, wherein the combination consists essentially of the digoxin or a digoxin and the turmeric extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.5 when tested in an in vitro assay.Q5. The method of claim QI, wherein the combination consists essentially of the digoxin or a digoxin and the turmeric extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.4 when tested in an in vitro assay.Q6. The method of any one of claims Q1-Q5, wherein the digoxin or the digoxin derivative and turmeric extract are delivered such that cancer cells are contactedwith a digoxin or a digoxin concentration of about 0.02 pg / mL and a turmeric extract concentration of about 10 pg / mL.Q7. The method of any one of claims Q1-Q6, wherein the turmeric extract is at least 95 wt% curcuminoids selected from the group consisting of curcumin, desmethoxycurcumin, bis-demethoxycurcumin and combinations thereof.Q8. The method of any one of claims Q1-Q7, wherein the combination is free of epigallocatechin-3-gallate (EGCG).Q9. The method of any one of claims Q1-Q7, wherein the combination is free of resveratrol.Q10. The method of any one of claims Q1-Q7, wherein the combination is free of both epigallocatechin-3-gallate (EGCG) and resveratrol.QI ’ A composition of matter comprising:a combination of a digoxin or a digoxin derivative and a turmeric extract.Q2’ . The composition of matter of claim QI’ , wherein the combination consists essentially of the digoxin or the digoxin derivative and the turmeric extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.8 when tested in an in vitro assay.Q3’. The composition of matter of claim QI’, wherein the combination consists essentially of the digoxin or the digoxin derivative and the turmeric extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.7 when tested in an in vitro assay.Q4’ . The composition of matter of claim QI ’ , wherein the combination consists essentially of the digoxin or the digoxin derivative and the turmeric extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.6 when tested in an in vitro assay.Q5’. The composition of matter of claim QI’, wherein the combination consists essentially of the digoxin or the digoxin derivative and the turmeric extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.5 when tested in an in vitro assay.Q6’ . The composition of matter of claim QI’ , wherein the combination consists essentially of the digoxin or the digoxin derivative and the turmeric extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.4 when tested in an in vitro assay.Q7’. The composition of matter of any one of claims Ql’-Q6’, wherein the composition exhibits a digoxin or the digoxin derivative concentration of about 0.02 pg / mL and a turmeric extract concentration of about 10 pg / mL.Q8’. The composition of matter of any one of claims QE-Q7’, wherein the combination is formulated as a tablet or a liquid.Q9’. The composition of matter of any one of claims Ql’-Q7’, wherein the combination is formulated as a liquid, a foam or a cream.Q10’. The composition of matter of any one of claims Ql’-Q7’, wherein the combination is formulated as an anal suppository.QI 1’. The composition of matter of any one of claims Ql’-Q10’, wherein the turmeric extract is at least 95 wt% curcuminoids selected from the group consisting of curcumin, desmethoxycurcumin, bis-demethoxycurcumin and combinations thereof.Q12’. The composition of matter of any one of claims Ql’-Ql 1’, wherein the combination is free of epigallocatechin-3-gallate (EGCG).Q13’. he composition of matter of any one of claims Ql’-Ql 1’, wherein the combination is free of resveratrol.Q14’. The composition of matter of any one of claims Ql’-Ql 1’, wherein the combination is free of both epigallocatechin-3-gallate (EGCG) and resveratrol.Rl. The method of any one of claims Nl-Nl 1, wherein the synergistic additive is a kava extract.R2. The method of claim Rl, wherein the combination consists essentially of the digoxin or the digoxin derivative and the kava extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.7 when tested in an in vitro assay.R3. The method of claim Rl, wherein the combination consists essentially of the digoxin or the digoxin derivative and the kava extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.6 when tested in an in vitro assay.R4. The method of claim Rl, wherein the combination consists essentially of the digoxin or the digoxin derivative and the kava extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.5 when tested in an in vitro assay.R5. The method of claim Rl, wherein the combination consists essentially of the digoxin or the digoxin and the kava extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.4 when tested in an in vitro assay.R6. The method of claim Rl, wherein the combination consists essentially of the digoxin or the digoxin and the kava extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.3 when tested in an in vitro assay.R7. The method of claim Rl, wherein the combination consists essentially of the digoxin or the digoxin and the kava extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.2 when tested in an in vitro assay.R8. The method of claim Rl, wherein the combination consists essentially of the digoxin or the digoxin and the kava extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.1 when tested in an in vitro assay.R9. The method of any one of claims R1-R8, wherein the kava extract and the digoxin or a digoxin are delivered such that cancer cells are contacted with a digoxin or a digoxin concentration of about 0.1 pg / mL and a kava extract concentration of about 30 pg / mL.RIO. The method of any one of claims R1-R8, wherein the kava extract and the digoxin or a digoxin are delivered such that cancer cells are contacted with a digoxin or a digoxin concentration of about 0.004 pg / mL and a kava extract concentration of about 30 pg / mL.Rl 1. The method of any one of claims R1-R10, wherein the kava extract comprises 40- 45 wt% dihydrokavain, 15-20 wt% kavain, 15-20 wt% dihydromethysticin, >0 but < 5 wt% methysticin, 5-10 wt% yangonin and 3-5 wt% demethoxyyangonin.Rl’. A composition of matter comprising:a combination of a digoxin or a digoxin derivative and a kava extract.R2’. The composition of matter of claim Rl’, wherein the combination consists essentially of the digoxin or the digoxin derivative and the kava extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.8 when tested in an in vitro assay.R3’. The composition of matter of claim Rl’, wherein the combination consists essentially of the digoxin or the digoxin derivative and the kava extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.7 when tested in an in vitro assay.R4’. The composition of matter of claim Rl’, wherein the combination consists essentially of the digoxin or the digoxin derivative and the kava extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.6 when tested in an in vitro assay.R5’. The composition of matter of claim Rl’, wherein the combination consists essentially of the digoxin or the digoxin derivative and the kava extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.5 when tested in an in vitro assay.R6’. The composition of matter of claim Rl’, wherein the combination consists essentially of the digoxin or the digoxin derivative and the kava extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.4 when tested in an in vitro assay.R7’. The composition of matter of claim Rl’, wherein the combination consists essentially of the digoxin or the digoxin derivative and the kava extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.3 when tested in an in vitro assay.R8’. The composition of matter of claim Rl’, wherein the combination consists essentially of the digoxin or the digoxin derivative and the kava extract such that the combination exhibits synergistic growth inhibition on HT29 colonadenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.2 when tested in an in vitro assay.R9’. The composition of matter of claim Rl’, wherein the combination consists essentially of the digoxin or the digoxin derivative and the kava extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.1 when tested in an in vitro assay.RIO’. The composition of matter of any one of claims Rl’-R9’, wherein the composition exhibits a digoxin or a digoxin derivative concentration of about 0.1 pg / mL and a kava extract concentration of about 30 pg / mL.Rl 1’. The composition of matter of any one of claims RU-R9’, wherein the composition exhibits a digoxin or a digoxin derivative concentration of about 0.004 pg / mL and a kava extract concentration of about 30 pg / mL.R12’. The composition of matter of any one of claims Rl’-Rl 1’, wherein the combination is formulated as a tablet or a liquid.R13’. The composition of matter of any one of claims Rl’-Rl 1’, wherein the combination is formulated as a liquid, a foam or a cream.R14’. The composition of matter of any one of claims Rl’-Rl 1’, wherein the combination is formulated as an anal suppository.R15’. The composition of matter of any one of claims Rl’-R14’, wherein the kava extract comprises 40-45 wt% dihydrokavain, 15-20 wt% kavain, 15-20 wt% dihydromethysticin, >0 but < 5 wt% methysticin, 5-10 wt% yangonin and 3-5 wt% demethoxyyangonin.51. The method of any one of claims Nl-Nl 1 , wherein the synergistic additive is 5- fluorouracil (5-FU).52. The method of claim SI, wherein the combination consists essentially of the digoxin or the digoxin derivative and the 5 -fluorouracil (5-FU) such that the combination exhibits synergistic growth inhibition on HT29 colonadenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.7 when tested in an in vitro assay.The method of claim SI, wherein the combination consists essentially of the digoxin or the digoxin derivative and the 5 -fluorouracil (5-FU) such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.6 when tested in an in vitro assay.The method of claim SI, wherein the combination consists essentially of the digoxin or the digoxin derivative and the 5-fluorouracil (5-FU) such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.5 when tested in an in vitro assay.The method of claim SI, wherein the combination consists essentially of the digoxin or the digoxin derivative and the 5-fluorouracil (5-FU) such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.4 when tested in an in vitro assay.The method of claim SI, wherein the combination consists essentially of the digoxin or the digoxin derivative and the 5-fluorouracil (5-FU) such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.3 when tested in an in vitro assay.The method of any one of claims S 1-S6, wherein the digoxin or the digoxin derivative and the 5-fluorouracil (5-FU) are delivered such that cancer cells are contacted with a digoxin or a digoxin derivative concentration of about 0.1 gg / mL and a 5-fluorouracil (5-FU) concentration of about 5 |ig / mL.The method of any one of claims S 1-S6, wherein the digoxin or the digoxin derivative and the 5-fluorouracil (5-FU) are delivered such that cancer cells arecontacted with a digoxin or a digoxin derivative concentration of about 0.02 pg / mL and a 5-fluorouracil (5-FU) concentration of about 2 pg / mL.SI’. A composition of matter comprising:a combination of a digoxin or a digoxin derivative and a 5 -fluorouracil (5-FU). S2’ . The composition of matter of claim SI’, wherein the combination consists essentially of the digoxin or the digoxin derivative and the 5-fluorouracil (5-FU) such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.8 when tested in an in vitro assay.S3’ . The composition of matter of claim SI’, wherein the combination consists essentially of the digoxin or the digoxin derivative and the 5-fluorouracil (5-FU) such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.7 when tested in an in vitro assay.S4’ . The composition of matter of claim SI’, wherein the combination consists essentially of the digoxin or the digoxin derivative and the 5-fluorouracil (5-FU) such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.6 when tested in an in vitro assay.S5 ’ . The composition of matter of claim SI’, wherein the combination consists essentially of the digoxin or the digoxin derivative and the 5-fluorouracil (5-FU) such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.5 when tested in an in vitro assay.S6’ . The composition of matter of claim SI’, wherein the combination consists essentially of the digoxin or the digoxin derivative and the 5-fluorouracil (5-FU) such that the combination exhibits synergistic growth inhibition on HT29 colonadenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.4 when tested in an in vitro assay.S7’ . The composition of matter of claim SI’, wherein the combination consists essentially of the digoxin or the digoxin derivative and the 5-fluorouracil (5-FU) such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.3 when tested in an in vitro assay.S8’. The composition of matter of any one of claims Sl’-S7’. wherein the composition exhibits a digoxin or a digoxin derivative concentration of about 0.1 pg / mL and a 5-fluorouracil (5-FU) concentration of about 5 pg / mL.S9’. The composition of matter of any one of claims SU-S7’. wherein the digoxin or the digoxin derivative and the 5-fluorouracil (5-FU) are delivered such that cancer cells are contacted with a digoxin or a digoxin derivative concentration of about 0.02 pg / mL and a 5-fluorouracil (5-FU) concentration of about 2 pg / mL. S10’. The composition of matter of any one of claims Sl’-S9’, wherein the combination is formulated as a tablet or a liquid.SIU. The composition of matter of any one of claims Sl’-S9’, wherein the combination is formulated as a liquid, a foam or a cream.S 12’. The composition of matter of any one of claims SU-S9’. wherein the combination is formulated as an anal suppository.Tl. The method of any one of claims Nl-Nll, wherein the synergistic additive is a ginger extract.T2. The method of claim Tl, wherein the combination consists essentially of the digoxin or the digoxin derivative and the ginger extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.7 when tested in an in vitro assay.T3. The method of claim Tl, wherein the combination consists essentially of the digoxin or the digoxin derivative and the ginger extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.6 when tested in an in vitro assay.T4. The method of claim Tl, wherein the combination consists essentially of the digoxin or the digoxin derivative and the ginger extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.5 when tested in an in vitro assay.T5. The method of claim Tl, wherein the combination consists essentially of the digoxin or the digoxin derivative and the ginger extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.4 when tested in an in vitro assay.T6. The method of claim Tl, wherein the combination consists essentially of the digoxin or the digoxin derivative and the ginger extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.3 when tested in an in vitro assay.T7. The method of claim Tl, wherein the combination consists essentially of the digoxin or the digoxin derivative and the ginger extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.2 when tested in an in vitro assay.T8. The method of claim Tl, wherein the combination consists essentially of the digoxin or the digoxin derivative and the ginger extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53mutant) cells such that the combination has a Combination Index (CI) of less than 0.1 when tested in an in vitro assay.T9. The method of any one of claims T1-T8, wherein the digoxin or the digoxin derivative and the ginger extract are delivered such that cancer cells are contacted with a digoxin or a digoxin derivative concentration of about 0.04 p.g / mL and a ginger extract concentration of about 0.8 p.g / mL.T10. The method of any one of claims T1-T8, wherein the digoxin or the digoxin derivative and the ginger extract are delivered such that cancer cells are contacted with a digoxin or a digoxin derivative concentration of about 0.004 pg / mL and a ginger extract concentration of about 20 pg / mL.TH. The method of any one of claims T1-T10, wherein the ginger extract is >20 wt% gingerols and shogaols, 8-10 wt% 6-gingerol, 2-3 wt% 8-gingerol, 3-4 wt% 10- gingerol, 2-3 wt% shogaols with the remainder being ginger polysaccharides, proteins, and native non-volatile components.Tl’ . A composition of matter comprising:a combination of a digoxin or a digoxin derivative and a ginger extract.T2’ . The composition of matter of claim Tl ’ , wherein the combination consists essentially of the digoxin or the digoxin derivative and the ginger extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.8 when tested in an in vitro assay.ls.T3’. The composition of matter of claim Tl’, wherein the combination consists essentially of the digoxin or the digoxin derivative and the ginger extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.7 when tested in an in vitro assay.T4’. The composition of matter of claim Tl’, wherein the combination consists essentially of the digoxin or the digoxin derivative and the ginger extract suchthat the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.6 when tested in an in vitro assay. T5’. The composition of matter of claim Tl’, wherein the combination consists essentially of the digoxin or the digoxin derivative and the ginger extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.5 when tested in an in vitro assay. T6’. The composition of matter of claim Tl’, wherein the combination consists essentially of the digoxin or the digoxin derivative and the ginger extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.4 when tested in an in vitro assay. T7’. The composition of matter of claim Tl’, wherein the combination consists essentially of the digoxin or the digoxin derivative and the ginger extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.3 when tested in an in vitro assay. T8’. The composition of matter of claim Tl’, wherein the combination consists essentially of the digoxin or the digoxin derivative and the ginger extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.2 when tested in an in vitro assay. T9’. The composition of matter of claim Tl’, wherein the combination consists essentially of the digoxin or the digoxin derivative and the ginger extract such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.1 when tested in an in vitro assay.T10’. The composition of matter of any one of claims Tl’-T9’, wherein the composition exhibits a digoxin or the digoxin derivative concentration of about 0.04 pg / mL and a ginger extract concentration of about 0.8 pg / mL.Til’. The composition of matter of any one of claims Tl’-T9’, wherein the digoxin or the digoxin derivative and the ginger extract are delivered such that cancer cells are contacted with a digoxin or a digoxin derivative concentration of about 0.004 pg / mL and a ginger extract concentration of about 20 pg / mL.T12’. The composition of matter of any one of claims Tl’-Tl 1’, wherein the combination is formulated as a tablet or a liquid.T13’. The composition of matter of any one of claims Tl’-Tl 1’, wherein the combination is formulated as a liquid, a foam or a cream.T14’. The composition of matter of any one of claims Tl’-Tl 1’, wherein the combination is formulated as an anal suppository.T15’. The composition of matter of any one of claims T1-T14, wherein the ginger extract is >20 wt% gingerols and shogaols, 8-10 wt% 6-gingerol, 2-3 wt% 8- gingerol, 3-4 wt% 10-gingerol. 2-3 wt% shogaols with the remainder being ginger polysaccharides, proteins, and native non-volatile components.U 1. A method for treating breast cancer in a patient, the method comprising:administering to the patient a therapeutically effective amount of a combination of a digoxin or a digoxin derivative and a therapeutically effective amount of simvastatin, wherein the combination exhibits a synergistic growth inhibition on MCF7 (ER+) breast cancer cells as determined by Bliss independence analysis with an Observed / Expected viability ratio of less than 1.0 when tested in an in vitro cell viability assay.U2. The method of claim Ul, wherein the digoxin or the digoxin derivative and the simvastatin are administered simultaneously.U3. The method of claim Ul, wherein the digoxin or the digoxin derivative and the simvastatin are administered sequentially such that the digoxin or the digoxin derivative and the simvastatin are simultaneously present in the patient.U4. The method of claim Ul, wherein the combination is administered orally.U5. The method of claim Ul, wherein the combination is administered orally, and the combination is formulated as a tablet or a liquid.U6. The method of claim Ul, wherein the combination is administered topically to a portion of the subject.U7. The method of claim U 1 , wherein the combination is administered rectally or by colonic delivery to a portion of the subject.U8. The method of claim Ul, wherein the combination is administered topically, and the combination is formulated as a liquid, a foam or a cream.U9. The method of claim Ul, wherein the combination is administered parenterally. U10. The method of any one of claims U1-U9, wherein the digoxin or the digoxin derivative and the simvastatin are delivered such that cancer cells are contacted with a digoxin or a digoxin derivative concentration of about 0.1 pg / mL and a simvastatin concentration between about 0.8 pg / mL and about 30 pg / mL.Ul.’ A composition of matter comprising:a combination of a digoxin or a digoxin derivative and a simvastatin.U2’ . The composition of matter of claim Ul ’ , wherein the combination consists essentially of the digoxin or the digoxin derivative and the simvastatin such that the combination exhibits a synergistic growth inhibition on MCF7 (ER+) breast cancer cells as determined by Bliss independence analysis with an Observed / Expected viability ratio of less than 1.0 when tested in an in vitro cell viability assay.U3’. The composition of matter of claim Ul’, wherein the composition exhibits a digoxin or a digoxin derivative concentration of about 0.1 pg / mL and a simvastatin concentration between about 0.8 pg / mL and about 30 pg / mL.U4’. The composition of matter of any one of claims UT-U3’, wherein the combination is formulated as a tablet or a liquid.U5’. The composition of matter of any one of claims Ul’-U3’, wherein the combination is formulated as a liquid, a foam or a cream.U6’. The composition of matter of any one of claims UT-U3’, wherein the combination is formulated as an anal suppository.

Claims

What is claimed is:

1. A method for treating colorectal cancer in a patient, the method comprising: administering to the patient a therapeutically effective amount of a combination of a rosemary extract and simvastatin, wherein the rosemary extract is an acetone extract of rosemary leaves comprising camosic acid, 12-O-methyl carnosic acid, and camosol, and wherein the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.8 when tested in an in vitro cell viability assay.

2. The method of claim 1, wherein the rosemary extract comprises 48±10 % camosic acid, 8±5 %, 12-O-methyl carnosic acid, and 3±2 % camosol, as determined by liquid chromatography.

3. The method of claim 1, wherein the rosemary extract comprises 48±5 % carnosic acid, 8+5 %. 12-O-methyl camosic acid, and 3+2 % camosol, as determined by liquid chromatography.

4. The method of claim 1, wherein the rosemary extract comprises 48±3 % carnosic acid, 8+2 %, 12-O-methyl camosic acid, and 3+1 % camosol, as determined by liquid chromatography.

5. The method of claim 1, wherein the combination consists essentially of the rosemary extract and the simvastatin such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.8 when tested in an in vitro cell viability assay.

6. The method of claim 1, wherein the combination has a CI of less than or equal to 0.7.

7. The method of claim 1, wherein the combination has a CI of less than or equal to 0.6.

8. The method of claim 1, wherein the combination has a CI of less than or equal to 0.5.

9. The method of claim 1, wherein the rosemary extract and simvastatin are administered simultaneously.

10. The method of claim 1, wherein the rosemary extract and simvastatin are administered sequentially such that both agents are present in the patient concurrently.

11. The method of claim 1, wherein the combination is administered orally.

12. A composition of matter comprising a combination of a rosemary extract and simvastatin, wherein the rosemary extract is an acetone extract of rosemary leaves comprising carnosic acid, 12-O-methyl camosic acid, and camosol.

13. The composition of claim 12, wherein the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.8 when tested in an in vitro cell viability assay.

14. The composition of claim 12, wherein the combination consists essentially of the rosemary extract and the simvastatin such that the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells such that the combination has a Combination Index (CI) of less than 0.8 when tested in an in vitro cell viability assay.

15. The composition of claim 12, wherein the rosemary extract comprises 48±10 wt% camosic acid, 8+5 wt%, 12-O-methyl camosic acid, and 3+2 wt% camosol.

16. The composition of claim 12, wherein the combination has a CI of less than or equal to 0.7.

17. The composition of claim 12, wherein the combination has a CI of less than or equal to 0.6.

18. A method of synergistically inhibiting growth of colon adenocarcinoma cells, the method comprising:contacting the colon adenocarcinoma cells with a combination of a rosemary extract and simvastatin, wherein the rosemary extract is an acetone extract of rosemary leaves comprising carnosic acid, 12-O-methyl carnosic acid, andcamosol, and wherein the combination exhibits synergistic growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells as determined by Bliss independence analysis with an Observed / Expected viability ratio of less than 1.0 when tested in an in vitro cell viability assay.

19. The method of claim 18, wherein the colon adenocarcinoma cells are contacted with the rosemary extract at a concentration of about 2 pg / mL and simvastatin at a concentration of about 2 pg / mL.

20. The method of claim 18, wherein the colon adenocarcinoma cells are contacted with the rosemary extract at a concentration of about 10 pg / mL and simvastatin at a concentration of about 0.8 pg / mL.

21. The method of claim 18, wherein the Observed / Expected viability ratio is less than or equal to 0.9.

22. The method of claim 18, wherein the Observed / Expected viability ratio is less than or equal to 0.7.

23. A method of synergistically inhibiting growth of colon adenocarcinoma cells, the method comprising:contacting the colon adenocarcinoma cells with a combination of a rosemary extract and simvastatin, wherein the combination exhibits excess growth inhibition on HT29 colon adenocarcinoma (TP53 mutant) cells beyond the highest single agent (AHSA > 0) as determined by comparison to the most effective single agent selected from the rosemary extract and the simvastatin.

24. The method of claim 23, wherein the AHSA is at least 10%.

25. The method of claim 23, wherein the AHSA is at least 20%.

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