Pharmaceutical composition for preventing or treating cancer comprising a CDK4 / 6 inhibitor and a tricyclic antidepressant

Abstract

An object of the present invention is to provide a composition for ameliorating, preventing, or treating cancer, which comprises a CDK4 / 6 inhibitor and a tricyclic antidepressant as active ingredients. When the composition containing the CDK4 / 6 inhibitor according to the present invention and a tricyclic antidepressant is administered in combination, it shows a synergistic anticancer effect, and the cancer cell survival rate is significantly reduced compared to the group treated with the CDK4 / 6 inhibitor or the antidepressant alone. In addition, the administration of the composition according to the present invention shows an effect of alleviating the side effects of the CDK4 / 6 inhibitor, so the composition containing the CDK4 / 6 inhibitor and the tricyclic antidepressant as active ingredients can be usefully used as a cancer prevention or treatment agent.

Description

Technical Field

[0001] The present invention relates to a composition for improving, preventing, or treating cancer, comprising a CDK4 / 6 inhibitor and tricyclic antidepressants as active ingredients.

Background Art

[0002] Cyclin-dependent kinase (hereinafter referred to as CDK) is an enzyme that regulates cell division and proliferation, and the progression of the cell cycle is controlled by cyclins and related CDKs. Most cancer cells exhibit characteristics in which CDK is not regulated, and CDK inhibition has emerged as a potential treatment for various cancers. CDK4 / 6 is responsible for the regulation that determines the process of progression from the G1 phase to the S phase during the cell cycle by phosphorylating and activating cyclin protein D1.

[0003] CDK4 / 6 inhibitors are drugs that block the formation of the CDK4 / 6-cyclin D1 complex and stop cell division. Three inhibitors, palbociclib, ribociclib, and abemaciclib, have been approved as therapeutic agents for HR(+), HER2(-), advanced or metastatic breast cancer (U.S. Pharm. 2020; 45(5)(Specialty&Oncology suppl):3-8.). Furthermore, clinical trials are being conducted using CDK4 / 6 inhibitors in combination therapy with letrozole or fulvestrant, drugs used in the treatment of breast cancer.

[0004] However, various side effects occur when using CDK4 / 6 inhibitors, but most side effects are low-risk side effects of grade 1 or 2, and side effects such as gastrointestinal disorders, neutropenia, and leukopenia of grade 3-4 are also reported to occur frequently. If side effects occur, measures to reduce side effects are taken by discontinuing the use of CDK4 / 6 inhibitors or reducing the dosage.

[0005] Meanwhile, in the case of cancer patients, depression is common due to the pain they experience during treatment, and antidepressants are often prescribed to resolve this, with prescriptions being administered in a range of concentrations. Side effects of antidepressants include insomnia, weight loss, dry mouth, and chest pain, but unlike the side effects of CDK4 / 6 inhibitors, it is known that dangerous side effects such as a decrease in blood cells do not occur (Oncology (Williston Park). 33 (2): 62-8.).

[0006] In addition, a study investigating the survival rate of cancer patients who use antidepressants showed that the use of antidepressants did not worsen the survival rate of cancer patients, and in particular, tricyclic antidepressants showed a significant increase in survival rate in lung cancer patients (reference: Cancer Treat Res Commun. 2017;10:33-39.).

[0007] Under these circumstances, the inventors have made intensive research efforts to develop a method for maximizing anti-cancer effects while minimizing side effects, and as a result, have confirmed that excellent anti-cancer effects are observed when a CDK4 / 6 inhibitor is administered in combination with a tricyclic antidepressant, thereby completing the present invention. Summary of the Invention technical challenges

[0008] An object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer, which comprises a CDK4 / 6 inhibitor and a tri-cyclic antidepressant as active ingredients.

[0009] The technical problem to be solved by the technical idea of ​​the invention disclosed in this specification is not limited to the problem of solving the problems mentioned above, and other problems not mentioned will be clearly understood by those skilled in the art from the following description.

[0010] This will be specifically described as follows. Meanwhile, each description and embodiment disclosed in this application can be applied to each other description and embodiment. That is, all combinations of various elements disclosed in this application belong to the scope of this application. Furthermore, the specific descriptions described below are not considered to limit the scope of this application.

[0011] In one embodiment to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating cancer, comprising a CDK4 / 6 inhibitor and a tri-cyclic antidepressant as active ingredients.

[0012] The term "CDK (Cyclin-dependent kinase)" as used herein refers to a cyclin-dependent protein kinase, which is a kinase that regulates the cell cycle and requires binding to cyclin for its activity. Among the CDK family, CDK4 and CDK6 phosphorylate the cyclin protein D1 to increase its activity, thereby regulating the progression from the G1 phase to the S phase during the cell cycle.

[0013] The term "CDK4 / 6 inhibitor" of the present invention means a drug that inhibits both CDK4 and CDK6, and CDK4 / 6 is used throughout this document to refer to both CDK4 and CDK6. The CDK4 / 6 inhibitor can be any drug that blocks the formation of CDK4 / 6-cyclin D complex and stops cell division, and specifically, it can be abemaciclib, ribociclib, palbociclib, or a pharmaceutically acceptable salt thereof.

[0014] The term "tricyclic antidepressant" as used herein refers to a drug that has three rings in its chemical structure and is one of the antidepressants that have been used for a long time as a psychotropic drug. It prevents the reabsorption of amine neurotransmitters secreted from nerve endings, allowing many of the substances to remain in the nerve junctions. Specifically, the tricyclic antidepressants include 7-OH-amoxapine, amezepine, amineptine, amitriptyline, amitriptylinoxide, amoxapine, aptazapine, azepindole, azipramine, Batelapine, Butriptyline, Cianopramine, Ciclazindol, Ciclopramine, Cidoxepin, Clomipramine, Cotriptyline, Cyanodothiepin, Demexiptilin e), Depramine (Valipramine), Desipramine (Desipramine (desmethylimipramine)), Desmethylclomipramine, Desmethyltrimipramine, Dibenzepin, Dimetacrine, Dosulepin (Dothiepin), Doxepin, Enprazepine, Esmirtazapine, Fantridone, Fluotracen, Hepzidine, Homopipramol, Imipramine, Imipraminoxide,Intriptyline, Iprindole, Ketipramine, Litracen, Lofepramine, Losindole, Loxapine, Maprotiline, Mariptiline, Mazindol, Melitracen, Metapramine apramine, mezepine, mianserin, mirtazapine, monometarine, naranol, nitroxazepine, norbutriptyline, nordoxepin, northiaden (nordosulepin), nortriptyline Nortriptyline (noramitriptyline), Noxiptiline, Octriptyline, Opipramol, Oxaprotiline, Pipofezine, Pirandamine, Promethazine, Propizepine, Protriptyline, Quinupramine, Setiptiline (teciptiline), Spiroxepin, Tandamine, Tampramine, Tianeptine, Tienopramine, Trimipramine, Imipramine Blue More specifically, the tricyclic antidepressant may be amitriptyline, clomipramine, desipramine, imipramine, promethazine, or imipramine blue.

[0015] The term "active ingredient" according to the present invention means an ingredient that exhibits a desired activity alone or that can exhibit an activity together with a carrier that is inactive by itself.

[0016] The term "cancer (or tumor)" of the present invention includes all cancers, regardless of whether they are primary cancers or metastatic cancers. In the present invention, the cancer may be a solid cancer or a blood cancer. Specifically, the cancer may be lung cancer, pancreatic cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer, duodenal cancer, small intestine cancer, colon cancer, colon cancer, rectal cancer, breast cancer, ovarian cancer, prostate cancer, liver cancer, thyroid cancer, kidney cancer, uterine cancer, brain tumor, skin cancer, melanoma, malignant bone tumor, bladder cancer, or blood cancer, but is not limited thereto. More specifically, the cancer may be lung cancer, colon cancer, or breast cancer.

[0017] The term "prevention" as used herein means any action of administering the pharmaceutical composition of the present invention to an individual to suppress or delay the onset of cancer.

[0018] The term "treatment" as used herein means any action of administering the pharmaceutical composition of the present invention to an individual to beneficially reverse, alleviate, or ameliorate cancer.

[0019] The pharmaceutical composition of the present invention may be for combined administration of a CDK4 / 6 inhibitor and a tricyclic antidepressant. Specifically, the pharmaceutical composition may be in the form of a mixture of a CDK4 / 6 inhibitor and a tricyclic antidepressant, or the CDK4 / 6 inhibitor and the tricyclic antidepressant may be formulated separately and administered simultaneously or sequentially, but is not limited thereto.

[0020] When a CDK4 / 6 inhibitor and a tricyclic antidepressant are co-administered, the administration concentration ratio of the CDK4 / 6 inhibitor and the tricyclic antidepressant may be 1:0.001 to 1:1000, specifically, 1:0.003 to 1:500, 1:0.01 to 1:500, 1:0.1 to 1:500, or 1:0.7 to 1:500, more specifically, 1:0.003, 1:0.01, 1:0.02, 1:0.03, 1:0.05, 1:0.08, It can be, but is not limited to, 1:0.1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:7, 1:8, 1:10, 1:11, 1:12, 1:20, 1:25, 1:100, 1:125, 1:200, or 1:500.

[0021] The pharmaceutical composition of the present invention may further include a pharma- ceutically acceptable carrier, excipient, or diluent according to a conventional method. Pharmaceutically acceptable carriers are well known in the art according to the route of administration or formulation, and may be found in the pharmacopoeias of various countries, including the Korean Pharmacopoeia. Carriers, excipients, and diluents that may be included in the composition of the present invention include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition, carriers, excipients, and diluents that may be included in the composition of the present invention may be, but are not limited to, non-natural carriers.

[0022] The pharmaceutical composition of the present invention can be formulated and used in the form of oral preparations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, or sterile injectable solutions according to the usual method. Specifically, it can be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants that are usually used in formulation. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations can be prepared by mixing the compound with at least one or more excipients, such as starch, calcium carbonate, sucrose, lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc can also be used. Liquid preparations for oral administration include suspensions, internal liquids, emulsions, syrups, etc., and in addition to the commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, flavorings, and preservatives are also included. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspensions can be propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, etc. Suppository bases can be witepsol, macrogol, twin 61, cacao butter, laurin butter, glycerogelatin, etc. Specific formulations of pharmaceutical compositions are known in the art, and can be found in, for example, Remington's Pharmaceutical Sciences (19th ed., 1995). The above-mentioned documents are considered as part of this specification.

[0023] The pharmaceutical composition of the present invention can be applied to any formulation containing a CDK4 / 6 inhibitor and a tricyclic antidepressant as active ingredients, and can be prepared into oral or parenteral formulations. Specifically, the administration method is not limited, but includes oral, rectal, nasal, topical (including buccal and sublingual), subcutaneous, vaginal, or parenteral (including intramuscular, subcutaneous, and intravenous) forms suitable for administration, or forms suitable for administration by inhalation or insufflation.

[0024] The pharmaceutical composition of the present invention is administered in a pharmacologic effective amount. The pharmacologic effective amount means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment and without causing side effects, and the effective dose level can be determined according to factors including the patient's health condition, the type and severity of the disease, the activity of the drug, the sensitivity to the drug, the administration method, administration time, administration route, and excretion rate, the duration of treatment, drugs used in combination or simultaneously, and other factors well known in the medical field. The amount and frequency of administration do not limit the scope of the present invention in any way.

[0025] The pharmaceutical compositions of the present invention can be administered to mammals, such as mice, dogs, cats, cows, horses, pigs, and humans, via a variety of routes. The present invention can be administered once a day, or can be administered in divided doses several times a day.

[0026] The pharmaceutical composition of the present invention can be used alone or in combination with various anti-cancer therapies commonly used in the art, such as surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers. In this sense, the pharmaceutical composition of the present invention can include an anti-cancer adjuvant form that enhances the anti-cancer effect of other anti-cancer drugs or suppresses or improves side effects.

[0027] As another aspect of the present invention for achieving the above object, there is provided a method for preventing or treating cancer, which includes administering the pharmaceutical composition to an individual in a pharmaceutically effective amount.

[0028] The term "individual" of the present invention includes, without limitation, animals such as mammals including mice, livestock, humans, etc. in which cancer may develop or has developed.

[0029] In the method for preventing or treating cancer of the present invention, the administration route of the pharmaceutical composition can be administered via any general route as long as it can reach the target tissue. The pharmaceutical composition of the present invention can be administered via various routes, such as oral administration, intravenous administration, rectal administration, etc., although not particularly limited thereto, and in some cases, it can also be administered via other routes depending on the purpose.

[0030] As another aspect of the present invention for achieving the above object, there is provided the use of a combination of a CDK4 / 6 inhibitor and a tricyclic antidepressant for the prevention or treatment of cancer; or the use of a composition containing a CDK4 / 6 inhibitor and a tricyclic antidepressant as active ingredients. As another aspect, there is provided the use of a combination of a CDK4 / 6 inhibitor and a tricyclic antidepressant; or a composition containing a CDK4 / 6 inhibitor and a tricyclic antidepressant for the manufacture of a medicament for the treatment or prevention of cancer.

Advantages of the Invention

[0031] When the composition containing a CDK4 / 6 inhibitor and a tricyclic antidepressant according to the present invention is administered in combination, it shows an anti-cancer synergistic effect, and the cancer cell survival rate is significantly decreased compared to the group treated with the CDK4 / 6 inhibitor or the antidepressant alone. In addition, by administering the composition according to the present invention, while obtaining a high anti-cancer effect, the side effects of the CDK4 / 6 inhibitor can be alleviated. Therefore, the composition containing a CDK4 / 6 inhibitor and a tricyclic antidepressant as active ingredients can be usefully used as a prophylactic or therapeutic agent for cancer.

Brief Description of the Drawings

[0032] [Figure 1a]FIG. 1a shows the results of measuring the change in tumor size over time when desipramine and abemaciclib were administered individually or in combination. [Figure 1b] FIG. 1b shows the results of comparing the tumor size between the single-administration and combination-administration groups 14 days after administration of desipramine and abemaciclib, respectively, or in combination. [Figure 2a] Figure 2a shows the results of hematoxylin and eosin staining of the heart, lungs, liver, spleen, and kidneys in the single- or combination-treated groups 14 days after administration of desipramine and abemaciclib, respectively, or in combination. [Figure 2b] Figure 2b shows the results of measuring the change in body weight of mice administered desipramine and abemaciclib alone or in combination over time. [Figure 3a] FIG. 3a shows the results of biochemical analysis of blood collected from mice 14 days after administration of desipramine and abemaciclib, respectively, or in combination. [Figure 3b] FIG. 3b shows the results of biochemical analysis of blood collected from mice 14 days after administration of desipramine and abemaciclib, respectively, or in combination. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0033] The present invention will be described in more detail with reference to the following examples, which are provided only to illustrate the present invention and are not intended to limit the scope of the present invention.

[0034] Example 1: Confirmation of the cancer cell killing effect by combined administration of CDK4 / 6 inhibitor and tricyclic antidepressant cell culture This experiment was performed with lung cancer cell line H460, colon cancer cell line HCT116, and breast cancer cell line MCF7. The genetic characteristics of each cell line are as follows: lung cancer cell line H460 has a KRAS mutation [p.Q61H], colon cancer cell line HCT116 has a KRAS mutation [p.G13D], and breast cancer cell line MCF7 is positive for estrogen receptor and progesterone receptor, but negative for HER2. H460 and MCF7 cell lines were cultured in RPMI1640 medium containing 10% FBS and 1% penicillin-streptomycin, and HCT116 cell line was cultured in McCoy's 5A medium containing 10% FBS and 1% penicillin-streptomycin.

[0035] 1.2. Confirmation of the effect of killing cancer cells Various combinations of CDK4 / 6 inhibitors and tricyclic antidepressants were used to confirm the cancer cell killing effect.

[0036] Specifically, abemaciclib, ribociclib, and palbociclib were used as CDK4 / 6 inhibitors, and DMSO was used as the solvent to make drug stocks. Imipramine, clomipramine, desipramine, amitriptyline, and imipramine blue were used as tricyclic antidepressants, and distilled water (DW) was used as the solvent to make drug stocks, with DMSO used only for imipramine blue. Each drug was diluted to the concentrations shown in Table 1 (antidepressant concentration (μM)) and Table 2 (CDK4 / 6 inhibitor concentration (μM)) below.

[0037] H460, HCT116, and MCF7 cell lines were cultured in 96-well plates at 3 × 10 3 The cells were cultured at 1000 cells / well. On the next day, each drug was prepared at the concentrations shown in Tables 1 and 2, mixed with the medium, and then placed in each well for 48 hours. After 48 hours, 10 ul / well of WST-1 reagent was added and reacted for 1 hour. The WST-1 reacted samples were analyzed by ELISA at 450 nM, and the same conditions were repeated three times to calculate the average value and standard error.

[0038] [Table 1]

[0039] [Table 2]

[0040] The experimental results for each cell line were observed as follows. (1) Anticancer efficacy test in lung cancer (cell line H460) The lung cancer cell survival rate when treated with 4 μM abecicrypt alone was 71%, and the survival rates of the antidepressant alone and combined treatment groups were as follows:

[0041] [Table 3]

[0042] As shown in Table 3, when CDK4 / 6 inhibitor Abemaciclib was treated with any of the antidepressants Imipramine, Clomipramine, Desipramine, Amitriptyline, and Imipramine Blue, the cancer cell viability was significantly decreased compared to the CDK4 / 6 inhibitor or antidepressant treatment alone, confirming the existence of an anticancer synergistic effect. The lung cancer cell viability was 72% when treated with 50μM Ribociclib alone, and the viability of the antidepressant treatment alone and combination treatment groups was as follows:

[0043] [Table 4]

[0044] As shown in Table 4, when ribociclib, a CDK4 / 6 inhibitor, was treated together with any one of the antidepressants imipramine, clomipramine, desipramine, amitriptyline, and imipramine blue, it was confirmed that the cancer cell survival rate was significantly decreased compared to the group treated with the CDK4 / 6 inhibitor or the antidepressant alone, and an anticancer synergistic effect appeared. The lung cancer cell survival rate at the time of treatment with 15 μM of palbociclib alone was 67%, and the survival rates of the antidepressant alone treatment group and the combined treatment group were shown as follows.

[0045]

Table 5

[0046] As shown in Table 5, when palbociclib, a CDK4 / 6 inhibitor, was treated together with any one of the antidepressants imipramine, clomipramine, desipramine, amitriptyline, and imipramine blue, it was confirmed that the cancer cell survival rate was significantly decreased compared to the group treated with the CDK4 / 6 inhibitor or the antidepressant alone, and an anticancer synergistic effect appeared.

[0047] (2) Anticancer efficacy test in colorectal cancer (cell line HCT116) The colorectal cancer cell survival rate at the time of treatment with 0.2 μM of abeciclib alone was 87%, and the survival rates of the antidepressant alone treatment group and the combined treatment group were shown as follows.

[0048]

Table 6

[0049] As shown in Table 6, when CDK4 / 6 inhibitor abemaciclib was treated with any of the antidepressants imipramine, clomipramine, desipramine, amitriptyline, and imipramine blue, the cancer cell viability was significantly decreased compared to the CDK4 / 6 inhibitor or antidepressant treatment groups alone, confirming the existence of an anticancer synergistic effect. The colon cancer cell viability was 73% when treated with 20μM ribociclib alone, and the viability of the antidepressant alone treatment group and the combination treatment group was as follows: [Table 7]

[0050] As shown in Table 7, when the CDK4 / 6 inhibitor ribociclib was treated together with any of the antidepressants imipramine, clomipramine, desipramine, amitriptyline, and imipramine blue, the cancer cell viability was significantly reduced compared to the groups treated with the CDK4 / 6 inhibitor or antidepressant alone, confirming the existence of an anticancer synergistic effect. The lung cancer cell viability was 79% when treated alone with palbociclib at 5μM, and the viability of the antidepressant alone and combined treatment groups was as follows:

[0051] [Table 8]

[0052] As shown in Table 8, when the CDK4 / 6 inhibitor palbociclib was treated together with any of the antidepressants imipramine, clomipramine, desipramine, amitriptyline, and imipramine blue, the cancer cell viability was significantly reduced compared to the groups treated with the CDK4 / 6 inhibitor or antidepressant alone, demonstrating a synergistic anticancer effect.

[0053] (3) Anticancer efficacy test in breast cancer (cell line MCF7) The breast cancer cell survival rate was 59% when treated with 10 μM abecicrypt alone, and the survival rates of the antidepressant alone and combined treatment groups were as follows:

[0054] [Table 9]

[0055] As shown in Table 9, when CDK4 / 6 inhibitor Abemaciclib was treated with any of the antidepressants Imipramine, Clomipramine, Desipramine, Amitriptyline, and Imipramine Blue, the cancer cell viability was significantly decreased compared to the CDK4 / 6 inhibitor or antidepressant treatment alone, confirming the existence of anticancer synergistic effects. The breast cancer cell viability was 80% when treated with 30μM Ribocicrypt alone, and the viability of the antidepressant treatment alone and combination treatment groups was as follows:

[0056] [Table 10]

[0057] As shown in Table 10, when the CDK4 / 6 inhibitor ribociclib was treated together with any of the antidepressants imipramine, clomipramine, desipramine, amitriptyline, and imipramine blue, the cancer cell viability was significantly reduced compared to the groups treated with the CDK4 / 6 inhibitor or antidepressant alone, confirming the existence of an anticancer synergistic effect. The breast cancer cell viability was 75% when treated with 20μM palbociclib alone, and the viability of the antidepressant alone and combination treatment groups was as follows:

[0058] [Table 11]

[0059] As shown in Table 11, when the CDK4 / 6 inhibitor palbociclib was treated together with any of the antidepressants imipramine, clomipramine, desipramine, amitriptyline, and amitriptyline, the cancer cell viability was significantly reduced compared to the groups treated with the CDK4 / 6 inhibitor or the antidepressant alone, demonstrating a synergistic anticancer effect.

[0060] Example 2: Analysis of the tumor growth inhibitory effect of combined administration of desipramine and abemaciclib 2.1. Construction of tumor models To evaluate the improved therapeutic effect of combined treatment with desipramine and abemaciclib, a subcutaneous tumor model was established using the colon cancer cell line HCT116.

[0061] Specifically, human colon cancer cell line HCT116 was purchased from the American Type Culture Collection (ATCC, USA) and cultured in McCoy's 5A medium containing 10% fetal bovine serum (FBS) and penicillin-streptomycin under conditions of 37°C, 5% carbon dioxide, and standard humidity. HCT116 cancer cells 5 × 10 6 Only 100μL of cells were injected subcutaneously into nude mice (Balb / c nude), and tumor formation was confirmed after about 7~10 days. The tumor size was 60~70mm. 3 When the mice reached the age of 18, they were divided into four groups (negative control group, desipramine monotherapy group, abemaciclib monotherapy group, and desipramine and abemaciclib combination therapy group) for the experiment. Desipramine was administered intraperitoneally at a dose of 20 mg / kg, and abemaciclib was administered orally at 30 mg / kg. Desipramine and abemaciclib were administered once daily until the end of the experiment, and the control group was administered vehicle.

[0062] 2.2. Analysis of tumor growth inhibition effect The antitumor effect was evaluated by measuring the tumor size every day until the 14th day after treatment and analyzing the differences between groups. The tumor size was expressed as V (mm 3) = 1 / 2 × major axis (mm) × minor axis (mm) × height (mm). The tumor size was measured by day 14 to create a tumor growth graph, and the tumor size between each group was compared. As can be seen from the results of Figure 1a and Figure 1b, the antitumor effect was confirmed to be the best in the desipramine and abemaciclib combination treatment group, and the tumor size in the desipramine alone treatment group, abemaciclib alone treatment group, and desipramine and abemaciclib combination treatment group on day 14 was measured as 75.2% (**P<0.01), 54.6% (***P<0.001), and 25.9% (***P<0.001) of the negative control group, respectively, confirming that the combination treatment had a synergistic anticancer effect compared to the single treatment group (Figure 1).

[0063] Example 3: Toxicity evaluation by drug administration To evaluate the in vivo toxicity of desipramine and abemaciclib, the major normal organs, heart, lungs, liver, spleen, and kidneys, were harvested on day 14, sectioned, and stained with hematoxylin and eosin to confirm the presence or absence of histological changes.

[0064] Histological examination of major organs in the groups administered desipramine and abemaciclib, individually or in combination, showed no histological changes compared to the control group (Figure 2a). In addition, body weight was measured for 14 days in the groups administered desipramine and abemaciclib, individually or in combination, and no significant difference in body weight was observed between the groups (Figure 2b).

[0065] On the 14th day of treatment, blood was collected from the mice and subjected to a biochemical analysis of the blood for groups administered desipramine and abemaciclib, either individually or in combination. No significant differences were observed in the various toxicity-related factors in the blood between the groups (Figure 3). Taking these results together, it was confirmed that the combined dose of desipramine and abemaciclib achieved a synergistic cancer treatment effect without causing toxicity to normal tissues.

Claims

1. It contains CDK4 / 6 inhibitors and tricyclic antidepressants as active ingredients, the CDK4 / 6 inhibitor is abemaciclib, ribociclib, or palbociclib; The tricyclic antidepressant is Amitriptyline, Clomipramine, Desipramine (desmethylimipramine), Imipramine, or Imipramine blue; A pharmaceutical composition for the prevention or treatment of cancer.

2. The pharmaceutical composition is for combined administration of a CDK4 / 6 inhibitor and a tricyclic antidepressant. The pharmaceutical composition for preventing or treating cancer according to claim 1.

3. The pharmaceutical composition is in the form of a mixed preparation in which the CDK4 / 6 inhibitor and the tricyclic antidepressant are mixed, or the CDK4 / 6 inhibitor and the tricyclic antidepressant are separately formulated and administered simultaneously or sequentially. The pharmaceutical composition for preventing or treating cancer according to claim 2.

4. The cancer is lung cancer, pancreatic cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer, duodenal cancer, small intestine cancer, large intestine cancer, colon cancer, rectal cancer, breast cancer, ovarian cancer, prostate cancer, liver cancer, thyroid cancer, kidney cancer, uterine cancer, brain cancer, skin cancer, melanoma, malignant bone tumor, bladder cancer, or blood cancer; The pharmaceutical composition for preventing or treating cancer according to claim 1.

5. The cancer is lung cancer, colon cancer, or breast cancer; The pharmaceutical composition for preventing or treating cancer according to claim 4.

6. The pharmaceutical composition further comprises a pharma- ceutically acceptable carrier, excipient, or diluent. The pharmaceutical composition for preventing or treating cancer according to claim 1.

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