Cancer treatment

Abstract

To provide drug administration regimens and drug combinations for use in the treatment of cancer.SOLUTION: The present invention is based on the finding that the inhibition of the proliferation of cancer cells by cannabinoids can be brought about more effectively by combined treatment with low dose naltrexone (LDN) or 6-β-naltrexone (6BN), a metabolite of naltrexone. Accordingly, there is provided a pharmaceutical composition comprising naltrexone, a metabolite thereof, or an analogue thereof, for use in the treatment of cancer within a subject, wherein a therapeutically effective amount of the naltrexone, metabolite thereof, or analogue thereof is administered to the subject in a first treatment phase, and wherein after the first treatment phase, a therapeutically effective amount of a cannabinoid is administered to the subject in a second treatment phase.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to drug administration regimens and drug combinations for use in the treatment of cancer. [Background technology]

[0002] Cannabinoids are a class of phenolic compounds that are abundantly produced in the Cannabis plant. Various cannabinoid compounds have long been known to have psychotropic effects in humans and are widely used recreationally, even though such use is illegal in many jurisdictions.

[0003] However, recent studies have demonstrated that some cannabinoids may be therapeutically useful for a wide range of conditions, including inflammatory diseases, neurodegenerative and psychiatric disorders, chronic pain, anxiety, and PTSD. While cannabinoids are currently used to combat the exhaustion, vomiting, and nausea associated with cancer treatment, there is evidence to suggest that some cannabinoid compounds may be effective in treating the underlying pathology of cancer. Currently available evidence suggests that these compounds do so by interfering with cancer cell migration, adhesion, and angiogenesis.

[0004] An endogenous cannabinoid-mediated signaling system is operative in mammals and, based on evidence, is likely to function in many other vertebrates. Two cannabinoid receptors have been identified in humans, termed CB1 and CB2. Both are part of the G protein-coupled receptor superfamily.

[0005] Current pharmacological evidence suggests that CB1 activation is responsible for most of the psychotropic effects of cannabinoid intake, whereas the majority of therapeutic effects are mediated by CB2. Therefore, an ideal therapeutic molecule would preferentially activate CB2 over CB1, thereby mitigating undesirable psychotropic effects. Cannabidiol (CBD), a component of cannabis extract, is a cannabinoid with this binding profile and has attracted considerable interest in recent years, although its mechanism of action remains unclear.

[0006] In general, however, natural cannabinoids do not tend to be highly specific for one receptor or the other, and newly developed synthetic cannabinoids, such as JWH-133 and SR141716 (Cridge & Rosengren 2013), are available that exhibit more specific binding. These compounds have been shown to inhibit tumor growth and cancer cell viability in vitro and in various tumor-bearing mouse models.

[0007] In response to a particular ligand, the expression level or downstream effects of a receptor in one signaling pathway can be altered seemingly by altering the signal output of another signaling pathway. Such cross-modulation has been demonstrated, for example, between the signaling pathways that follow activation of growth hormone and insulin receptors. Summary of the Invention

[0008] The present inventors have discovered that cannabinoids can more effectively inhibit cancer cell growth by combined treatment with low-dose naltrexone (LDN) or naltrexone metabolite 6-β-naltrexol (6BN). The inventors have discovered that the effectiveness of such treatment is surprisingly dependent on the order in which the two agents are administered, with the most effective regimen being one in which a treatment phase with LDN or 6BN is followed by a treatment phase with a cannabinoid.

[0009] The inventors also discovered a previously unknown fact that treatment with LDN or 6BN significantly increases the amount of CB2 receptors in cancer cells, making cannabinoids more effective.

[0010] According to a first aspect of the present invention, there is provided a pharmaceutical composition comprising naltrexone, a metabolite thereof, or an analogue selected from the group consisting of methylnaltrexone, naloxone, nalmefene, and nalorphine for use in treating cancer in a subject, wherein a therapeutically effective amount of the naltrexone, metabolite thereof, or analogue is administered to the subject in a first treatment phase, and following the first treatment phase, a therapeutically effective amount of a cannabinoid is administered to the subject in a second treatment phase.

[0011] According to a second aspect of the present invention, there is provided a pharmaceutical composition comprising a cannabinoid for use in treating cancer in a subject, wherein the subject undergoes a first treatment phase in which a therapeutically effective amount of naltrexone, a metabolite thereof, or an analogue selected from the group consisting of methylnaltrexone, naloxone, nalmefene, and nalorphine is administered, and after the first treatment phase, a therapeutically effective amount of the cannabinoid is administered to the subject.

[0012] According to a third aspect of the present invention, there is provided a formulation comprising naltrexone, a metabolite thereof, or an analog selected from the group consisting of methylnaltrexone, naloxone, nalmefene, and nalorphine; and a cannabinoid; for use in treating cancer in a subject, wherein the naltrexone, metabolite, or analog is provided in a therapeutically effective amount for administration in a first treatment phase, and the cannabinoid is provided in a therapeutically effective amount for administration in a second treatment phase following the first treatment phase.

[0013] According to a fourth aspect of the present invention there is provided a method for determining the suitability of a subject having cancer for treatment with a cannabinoid in a second treatment phase, said subject being characterised by having undergone a first treatment phase as defined above, said method comprising: i. contacting a sample obtained from said subject after or during a recovery phase with a probe specific for CB2; ii. determining the concentration of CB2 in the sample; iii. comparing the concentration of CB2 in the sample with the concentration of CB2 determined from a sample obtained from the subject prior to the first treatment phase; wherein the subject is suitable for the second treatment phase if the CB2 concentration increases by at least two-fold after the first treatment phase.

[0014] According to a fifth aspect of the present invention, there is provided the use of naltrexone, a metabolite thereof, or an analogue selected from the group consisting of methylnaltrexone, naloxone, nalmefene, and nalorphine in the manufacture of a medicament for the treatment of cancer in a subject, wherein the medicament is administered to the subject in a first treatment phase of a combination treatment regimen, the treatment regimen comprising the first treatment phase followed by a second treatment phase, and the subject is administered a cannabinoid in the second treatment phase.

[0015] According to a sixth aspect of the present invention there is provided the use of a cannabinoid in the manufacture of a medicament for the treatment of cancer in a subject, said medicament being administered in a second treatment phase of a combination treatment regimen comprising a first treatment phase followed by said second treatment phase, said subject being administered in said first treatment phase naltrexone, a metabolite thereof or an analogue selected from the group consisting of methylnaltrexone, naloxone, nalmefene and nalorphine.

[0016] According to a seventh aspect of the present invention there is provided the use of naltrexone, a metabolite thereof or an analogue selected from the group consisting of methylnaltrexone, naloxone, nalmefene and nalorphine in the manufacture of a first medicament, and the use of a cannabinoid in the manufacture of a second medicament, both of which are for the treatment of cancer, the first and second medicaments being administered to a subject having cancer in a combined treatment regimen comprising a first treatment phase followed by a second treatment phase, the first medicament being administered to the subject in the first treatment phase and the second medicament being administered to the subject in the second treatment phase.

[0017] According to an eighth aspect of the present invention, there is provided a method for treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of naltrexone, a metabolite thereof, or an analogue selected from the group consisting of methylnaltrexone, naloxone, nalmefene, and nalorphine in a first treatment step, and then administering to the subject a therapeutically effective amount of a cannabinoid in a second treatment step. [Brief explanation of the drawings]

[0018] [Figure 1] Figure 1 shows the effects of 2-day treatment of cultures of the MCF7 breast cancer cell line with 10 nM naltrexone (LDN), 1 μM 6-β-naltrexol (6-1), or 10 μM 6-β-naltrexol (6-2). The levels of Bcl2-associated death promoter (BAD), p21 protein, opioid receptors kappa 1 (OPRK1) and μ1 (OPRM1), and cannabinoid receptors CBR1 (CB1) and CBR2 (CB2) were visualized by Western blotting (left) using GAPDH as a loading control and quantified by analysis of relative concentrations to GAPDH (right). [Figure 2]Figure 2 shows the effect of various two-step treatments on the proliferation and viability of MCF7 cells. Each treatment lasted for 4 days, with 2 days of treatment with the first drug (UN = control, LDN = 10 nM low-dose naltrexone, CBD = cannabidiol, 6BN = 6-β-naltrexol) followed by 2 days of introduction of the second drug. DETAILED DESCRIPTION OF THE INVENTION

[0019] The present invention provides a particular therapeutic regimen for treating cancer in a subject, in which a cannabinoid is administered following administration of low-dose naltrexone (LDN), a metabolite of naltrexone, or an analog selected from the group consisting of methylnaltrexone, naloxone, nalmefene, and nalorphine.

[0020] The inventors have found that administering LDN followed by a cannabinoid in a stepwise manner inhibits cancer cell growth more effectively than administering them separately or simultaneously, or than administering a cannabinoid followed by LDN in a stepwise manner.

[0021] Furthermore, it was shown that the amount of CB2 receptors in MCF7 cells was significantly increased after treatment with LDN. Without being bound by theory, this increase in CB2, the therapeutic target of cannabinoids such as CBD, is a favorable factor contributing to the improved efficacy of CBD treatment.

[0022] Those skilled in the art will be able to perform stepwise administration of the therapeutic agents as described above. The present invention can be further understood by reference to the following definitions.

[0023] As used herein, the term "naltrexone" refers to the compound 17-cyclopropylmethyl-4.5α-epoxy-3,14-dihydroxymorphinan-6-one (IUPAC name (4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one) and its pharmacologically acceptable salts, solvates, hydrates, racemates, stereoisomers, clathrates, polymorphs, and prodrugs. The use of analogs thereof in accordance with the present invention is also contemplated. Examples of suitable analogs include methylnaltrexone, naloxone, nalmefene, and nalorphine.

[0024] The naltrexone is typically in the form of its hydrochloride salt.

[0025] "Low-dose naltrexone" (LDN) refers to naltrexone administered at "low" doses of less than 0.5 mg / kg, preferably less than 0.2 mg / kg, more preferably 0.01 mg / kg to 0.08 mg / kg, even more preferably 0.03 mg / kg to 0.06 mg / kg, and most preferably 0.04 mg / kg to 0.05 mg / kg. Typically, low doses are up to a total of 3 mg / day per patient.

[0026] Examples of metabolites of naltrexone include 6-β-naltrexol, 2-hydroxy-3-methoxy-6β-naltrexol, and 2-hydroxy-3 methoxy-naltrexone.

[0027] The preferred metabolite of naltrexone is 6-β-naltrexol (6BN), which is referred to herein as the compound N-cyclopropylmethyl-7,8-dihydro-14-hydroxynorisomorphine (IUPAC name (4R,4aS,7R,7aR,12bS)-3-(cyclopropylmethyl)-1,2,4,5,6,7,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7,9-triol) and its pharmacologically acceptable salts, solvates, hydrates, racemates, stereoisomers, clathrates, polymorphs, and prodrugs.

[0028] The 6BN or analogue may also be administered at a "low dose." In this context, a "low dose" may be as outlined above for naltrexone.

[0029] Those skilled in the art will recognize that cannabinoids are a class of compounds that includes endocannabinoids synthesized in animals as well as those abundantly produced by plants in the Cannabis genus. Synthetic compounds active at CB receptors are also contemplated. As used herein, the term may refer to any cannabinoid, but is preferably selected from the list comprising cannabidiol, cannabidiolic acid, cannabinol, cannabigerol, cannabivarin, tetrahydrocannabivarin, cannabidivarin, cannabichromene, arachidonoylethanolamine, 2-arachidonoylglycerol, 2-arachidonoylglyceryl ether, N-arachidonoyldopamine, virodamine, dronabinol, nabilone, rimonabant, R-(+)-Met-anandamide, WIN-55,212-2, HU-210, JWH-133, SR141716, SR144528, or combinations thereof, or pharmacologically acceptable salts, solvates, hydrates, racemates, stereoisomers, clathrates, polymorphs, prodrugs, and analogues thereof that produce equivalent effects.

[0030] In one embodiment, when the agent is 6-β-naltrexol, the 6-β-naltrexol is administered in an amount effective to increase the plasma concentration of 6-β-naltrexol to at least 0.34 ng / ml, preferably at least 3.4 ng / ml, more preferably at least 34 ng / ml, or most preferably at least 340 ng / ml. In one embodiment, the 6-β-naltrexol is administered in an amount effective to increase the plasma concentration of 6-β-naltrexol to a range of 0.3 ng / ml to 3400 ng / ml, preferably 34 ng / ml to 3400 ng / ml, more preferably 340 ng / ml to 3400 ng / ml. Amounts effective to achieve such amounts can be determined using any number of conventional methods known to those of skill in the art. For example, one skilled in the art can perform mass spectrometry on plasma samples obtained from a subject to determine the increase in 6-β-naltrexol concentration in the sample after administration of a certain amount of 6-β-naltrexol. An effective amount is an amount determined to result in a desired increase in plasma concentration. Typically, naltrexol is administered in amounts up to 3 mg per patient per day.

[0031] The cannabinoids may be administered in conventional amounts based on the particular cannabinoid and patient details, hi one embodiment, the cannabinoids are administered in dosages of 10 mg to 1000 mg per day, preferably 200 to 800 mg, more preferably 300 to 500 mg.

[0032] As used herein, the term "formulation" can refer to a substance or collection of substances in the form of one or more compositions intended for simultaneous or non-simultaneous use.

[0033] Although the method of administration is not limited to either therapeutic agent, in various embodiments of the invention, LDN and cannabinoids are administered orally, buccally, sublingually, nasally, pulmonary, intravenously, rectally, topically, and transdermally. LDN is preferably administered orally, and cannabinoids are preferably administered sublingually.

[0034] The contemplated treatment regimen includes a "first treatment phase" and a "second treatment phase." In the first treatment phase, a therapeutically effective amount of LDN, its metabolites, or any analogs is administered. In the second treatment phase, an effective amount of one or more cannabinoids is administered.

[0035] The second treatment phase is preferably initiated 1 to 7 days after the start of the first treatment phase, more preferably 1 to 4 days, and most preferably 1 to 2 days, where "day" refers to any consecutive 24-hour period.

[0036] In a further preferred embodiment of the present invention, there is a "recovery phase" between the end of the first treatment phase and the beginning of the second treatment phase. During the recovery phase, LDN or cannabinoids are not administered. In one embodiment, the recovery phase has a duration of at least 2 days, preferably no more than 1 week, and most preferably 2 days.

[0037] As used herein, the terms "treating" and "treatment" and "to treat" refer to both therapeutic measures that cure, slow, and / or halt the progression of a diagnosed condition or disease, and prophylactic or preventative measures that prevent and / or delay the onset of the targeted condition or disease. Thus, subjects in need of treatment include those already with the disease, those prone to having the disease, and those in whom the disease is to be prevented. In some instances, a subject's tumor / cancer will be successfully "treated" in accordance with the present invention if the subject exhibits one or more of the following: a reduction in the number of cancer cells or the complete absence of cancer cells; a reduction in tumor size; inhibition or absence of cancer cell invasion into surrounding organs, such as the spread of cancer to soft tissue and bone; inhibition or absence of tumor metastasis; inhibition or absence of tumor growth; a reduction in morbidity and mortality; a reduction in tumorigenicity, tumor frequency, or tumorigenic potential of the tumor; a reduction in the number or frequency of cancer stem cells within the tumor; differentiation of tumor-forming cells into non-tumorigenic cells; or a combination of multiple effects.

[0038] As used herein, the term "subject" refers to any animal, including but not limited to humans, non-human primates, horses, dogs, cats, rodents, and other vertebrates, to be treated for cancer. The terms "subject" and "patient" are used interchangeably herein.

[0039] As used herein, the term "tumor / cancer" refers to any mass of tissue resulting from excessive growth, proliferation, and / or survival of cells, and includes either benign (non-cancerous) or malignant (cancerous) tissue, including pre-cancerous lesions.

[0040] The types of cancer that can be treated by the present invention are not limited in any way, but include, for example, carcinoma, sarcoma, adenocarcinoma, melanoma, neuro(blastoma, glioma), mesothelioma, and neoplastic diseases of the reticuloendothelial, lymphatic, or hematopoietic systems (myeloma, lymphoma, or leukemia). In specific embodiments, the tumors may include lung adenocarcinoma, lung cancer, diffuse or stromal gastric cancer, colon adenocarcinoma, prostate adenocarcinoma, esophageal cancer, breast cancer, pancreatic adenocarcinoma, ovarian adenocarcinoma, adrenal adenocarcinoma, and endometrial or uterine adenocarcinoma, although the type of cancer is preferably breast cancer.

[0041] In a preferred embodiment, the cancer to be treated is selected from brain, breast, colon, lung, prostate, and pancreatic cancer, and leukemia. The cancer to be treated is preferably breast cancer.

[0042] The definition of "breast cancer" is well known in medicine. Those skilled in the art recognize that breast cancer refers to any malignant tumor of male or female breast tissue, such as carcinoma or sarcoma. Specific forms of breast cancer include ductal carcinoma in situ (DCIS), lobular carcinoma in situ (LCIS), or mucinous carcinoma. Breast cancer also refers to invasive ductal carcinoma (IDC), lobular neoplasm, or invasive lobular carcinoma (ILC).

[0043] As used herein, the term "cancer cell" refers to a cell or immortalized cell line derived from a tumor or cancer.

[0044] In one aspect of the present invention, a method is provided for determining the suitability of a subject with cancer who has been treated with LDN for treatment with a cannabinoid. In this aspect, a sample is obtained from the subject and contacted with a CB2-specific probe. The concentration of CB2 in the sample is thereby determined and compared with a baseline measurement made before the first treatment phase.

[0045] The term "suitability" as used herein refers to the property of having a higher probability of success in treatment as defined above compared to subjects deemed unsuitable by the test. A subset of subjects who undergo testing by the method envisioned in one aspect of the present invention will be deemed unsuitable for the second stage of treatment. Nothing in the present invention prohibits use with such subjects. The method of determining suitability is intended to be considered by those skilled in the art, using intuition and judgment in conjunction with other known tests.

[0046] In certain embodiments, the biological "sample" obtained from a subject for use in the method is blood, plasma, serum, lymph, tissue, or cells from a tissue sample, although preferably the sample is a tumor biopsy obtained from the subject.

[0047] As used herein, a "probe" refers to any component that, when contacted with a sample obtained from a subject, allows for the measurement of the CB2 concentration in the sample in some manner. In one embodiment, the probe is an antibody or other CB2-binding molecule used to provide a purer CB2 solution that can be analyzed spectrophotometrically and calibrated by methods known to those skilled in the art, thereby determining the concentration of CB2 in the original sample. can.

[0048] In another aspect, there is provided the use of naltrexone, a metabolite thereof, or an analog selected from the group consisting of methylnaltrexone, naloxone, nalmefene, and nalorphine; and a cannabinoid; in the manufacture of a medicament to be administered as part of a "combination therapeutic regimen," wherein said "combination therapeutic regimen" refers to a regimen consisting of a first therapeutic phase, and preferably a recovery phase, and a second therapeutic phase, as defined above.

[0049] The invention will now be described with reference to the following non-limiting examples. [Example]

[0050] Example 1 One illustrative, non-limiting experiment was performed on cultures of MCF7 cells. Briefly, either 10 nM LDN or 1 μM or 10 μM 6BN was administered in Cultures were treated in vitro for 2 days, after which the expression levels of BAD, p21, opioid receptors κ and μ, CB1, CB2, and GAPDH (as a loading control) were analyzed by Western blotting and subsequent quantification by band densitometry.

[0051] Specifically, MCF7 cells were seeded at a density of 1 × 105 / well in 6-well plates and allowed to adhere overnight. Naltrexone (10 nM) or 6-β-naltrexol (1 μM or 10 μM) was added to the cells, followed by harvesting and Western blot analysis. Specific antibodies raised against BAD, p21, OPRK1, OPRK2, CBR-1, and CBR-2 were used as primary probes. BAD is a Bcl2-associated death promoter. It is a proapoptotic protein whose upregulation in cancer cells increases the susceptibility of cells to killing by various therapies. Anti-GAPDH was used as a loading control. All antibodies were used at a 1:1000 dilution, followed by the appropriate HRP-conjugated secondary antibody at a 1:1000 dilution. Bands were visualized using the SuperSignal chemiluminescent detection system, and band densitometry was performed using Adobe Photoshop CS3, v10.0 and normalized to loading controls.

[0052] All three treatments increased the levels of CB2 and BAD compared to untreated controls. For CB2, this increase was greatest with 10 μM 6BN. See Figure 1.

[0053] Example 2 Another illustrative, non-limiting experiment was carried out on MCF7 cell cultures. Briefly, cultures were treated with LDN or 6BN for 2 days, and then administered with cannabinoids for another 2 days. Cell count and viability were assessed on the fourth day. The administration order of each treatment agent was reversed, and the experiment was repeated.

[0054] Specifically, MCF7 cells were seeded in 6-well plates at a density of 1.5 x 104 / well and allowed to adhere. The cells were then cultured with naltrexone (10 nM), 6-β-naltrexol (10 μM), or cannabidiol (10 μM). After 48 hours, the drug-containing medium was removed, and the cells were gently rinsed with drug-free medium. Fresh medium containing either naltrexone (10 nM), 6-β-naltrexol (10 μM), or cannabidiol (10 μM), as indicated in the graph, was then added to the cells. For an additional 4 After 8 hours, cell number and viability were assessed by the percentage of live and dead cells as identified by trypan blue dye exclusion. Data were then pooled to compare the effect of sequence on overall efficacy.

[0055] As can be seen in Figure 2, schedules in which LDN or 6BN was used prior to the cannabinoid were more effective in inhibiting cancer growth.

[0056] literature Cridge, B. & Rosengren, R (2013) Critical appraisal of the potential use of cannabinoids in cancer management. Cancer Management and Research 2013:5 301-313

Claims

1. 1. A pharmaceutical composition comprising naltrexone; a metabolite of naltrexone selected from the group consisting of 6-β-naltrexol, 2-hydroxy-3-methoxy-6β-naltrexol, and 2-hydroxy-3-methoxy-naltrexone; or an analog selected from the group consisting of methylnaltrexone, naloxone, nalmefene, and nalorphine; for use in treating cancer in a subject, wherein a therapeutically effective amount of the naltrexone, the metabolite, or either of the analogs is administered to the subject in a first treatment phase, and following the first treatment phase, a therapeutically effective amount of a cannabinoid is administered to the subject in a second treatment phase.

2. 1. A pharmaceutical composition comprising a cannabinoid for use in treating cancer in a subject, wherein the subject has undergone a first treatment phase in which the subject is administered a therapeutically effective amount of naltrexone; a metabolite of naltrexone selected from the group consisting of 6-β-naltrexol, 2-hydroxy-3-methoxy-6β-naltrexol, and 2-hydroxy-3-methoxy-naltrexone; or an analog selected from the group consisting of methylnaltrexone, naloxone, nalmefene, and nalorphine; and after the first treatment phase, a therapeutically effective amount of the cannabinoid is administered to the subject.

3. 1. A formulation for use in treating cancer in a subject, comprising: naltrexone; a metabolite of naltrexone selected from the group consisting of 6-β-naltrexol, 2-hydroxy-3-methoxy-6β-naltrexol, and 2-hydroxy-3-methoxy-naltrexone; or an analog selected from the group consisting of methylnaltrexone, naloxone, nalmefene, and nalorphine; and a cannabinoid, wherein the naltrexone, the metabolite, or either of the analogs is provided in a therapeutically effective amount for administration in a first treatment phase, and the cannabinoid is provided in a therapeutically effective amount for administration in a second treatment phase following the first treatment phase.

4. The pharmaceutical composition or formulation according to any one of claims 1 to 3, wherein the first treatment phase is for administration for at least two days.

5. 5. The pharmaceutical composition or formulation of any one of claims 1 to 4, wherein the first and second treatment phases are separated by a recovery phase, the recovery phase being characterized by the absence of administration of any of the naltrexone, metabolites, analogs, and cannabinoids.

6. 6. The pharmaceutical composition or formulation of claim 5, wherein the recovery phase lasts for at least one day.

7. The pharmaceutical composition or formulation according to claim 5, wherein the recovery phase is within a range of 1 to 7 days.

8. The pharmaceutical composition or formulation according to any one of claims 1 to 7, wherein the second treatment phase is for administration for at least one day.

9. The pharmaceutical composition or formulation of any one of claims 1 to 8, wherein the composition or formulation comprises naltrexone.

10. The pharmaceutical composition or formulation of any one of claims 1 to 9, wherein the composition or formulation comprises 6-β-naltrexol.

11. The cannabinoid may be cannabidiol, cannabidiolic acid, cannabinol, 11. The pharmaceutical composition or formulation of any one of claims 1 to 10, wherein the active ingredient is selected from the list consisting of: cannabigerol, cannabivarin, tetrahydrocannabivarin, cannabidivarin, cannabichromene, arachidonoylethanolamine, 2-arachidonoylglycerol, 2-arachidonoylglyceryl ether, N-arachidonoyldopamine, virodamine, dronabinol, nabilone, rimonabant, or a combination thereof.

12. 12. A pharmaceutical composition or formulation according to any one of claims 1 to 11, wherein the cannabinoid is cannabidiol.

13. The pharmaceutical composition or formulation according to any one of claims 1 to 12, wherein the cancer is breast cancer.

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