WO2022055285A1 - Pharmaceutical composition for killing cancer progenitor cells - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for killing cancer progenitor cells, comprising perphenazine and a biguanide-based compound or a glucose uptake inhibitor as active ingredients. The pharmaceutical composition of the present invention not only can effectively ameliorate or treat cancer by specifically killing cancer progenitor cells, but furthermore can also prevent the onset of cancer itself or the recurrence of cancer.

Description

Pharmaceutical composition for killing cells of origin of cancer

The present invention relates to a pharmaceutical composition capable of radically treating cancer by killing cells of origin, as well as preventing the onset or recurrence of cancer.

Cancer is a cell mass composed of undifferentiated cells that proliferate indefinitely while ignoring the necessary condition in the tissue, unlike normal cells, which can proliferate and suppress regularly and in a controlled manner according to individual needs. Such unrestricted proliferation of cancer cells infiltrates into surrounding tissues and, in more severe cases, metastasizes to other organs of the body, causing severe pain and eventually death.

According to data from the American Cancer Society, more than 12 million new cancer cases were diagnosed worldwide in 2007, and 7.6 million deaths were reported, with an estimated 20,000 deaths from cancer every day. In Korea, according to a report by the National Statistical Office in 2006, cancer-related deaths were the number one cause of death. Therefore, there is an urgent need to develop an oncology therapeutic agent with excellent therapeutic effect to reduce mental and physical pain and improve quality of life due to cancer occurrence and battle.

However, despite many efforts, it has not yet been clarified precisely how normal cells are transformed into cancer cells. Factors are intricately intertwined, resulting in cancer. Genes involved in the development of cancer include oncogenes and tumor suppressor genes, and cancer occurs when the balance between them is disrupted by the internal or external factors described above.

Cancer is broadly classified into blood cancer and solid cancer. Although therapeutic agents are being used to treat specific cancers, up to now, surgery, radiation therapy, and chemotherapy using chemotherapeutic agents that inhibit cell proliferation are the main methods. However, since it is not a targeted treatment, the biggest problem with existing chemotherapeutic agents is side effects and drug resistance due to cytotoxicity, which is a major factor that ultimately leads to treatment failure despite the initial successful response to anticancer drugs. Therefore, in order to overcome the limitations of these chemotherapeutic agents, there is a continuous need to develop targeted therapeutics with a clear anticancer mechanism.

On the other hand, glioma (glioma) is a tumor that accounts for 60% of primary brain tumors, it is a malignant tumor that has a high incidence and difficult to treat, and there is no special treatment other than radiation therapy to date. In the case of glioblastoma (GBM), which is classified as the most malignant among them, compared to other cancers, the resistance to radiation and chemotherapy is very high, and once diagnosed, the survival period is only one year. A proper diagnosis and understanding of the origin and process is important.

In addition, in the case of the brain tumor, it is difficult to deliver a drug for treatment to a target brain region because a brain blood barrier exists, and development of a therapeutic agent is difficult due to a relatively lack of understanding of brain neurobiology. The reality is that it is not active. Moreover, glioblastoma exhibits an aggressive variant compared to other brain tumors, which, if not treated promptly, can have fatal consequences within a few weeks.

Therefore, in the treatment of glioblastoma, radiation therapy and chemical drug treatment are performed together in addition to surgical treatment, but there is no perfect treatment for the treatment due to causes such as occurrence of resistance mutation and recurrence by tumor stem cells.

Recently, it has been found that the cells of origin of the glioblastoma correspond to cells in the subventricular region and cells migrated from the subventricular region (Korean Patent Publication No. 10-2019-0095074). Therefore, for the effective treatment of glioblastoma, there is a need for early diagnosis and understanding of the origin of the development and development of a new treatment method based thereon.

One object of the present invention is to provide a pharmaceutical composition capable of fundamentally treating cancer by killing cells of origin, as well as preventing the onset or recurrence of cancer.

Another object of the present invention is to provide a method capable of fundamentally treating cancer by killing cells of origin, as well as preventing the onset or recurrence of cancer.

However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problems, and other problems not mentioned will be clearly understood by those of ordinary skill in the art from the following description.

According to one embodiment of the present invention, it relates to a pharmaceutical composition for killing cells of origin.

According to another embodiment of the present invention, it relates to a pharmaceutical composition for preventing or treating cancer.

The pharmaceutical composition provided in the present invention,

(1) perphenazine or a pharmaceutically acceptable salt thereof; and

(2) any one of a biguanide-based compound and a glucose uptake inhibitor; Or a pharmaceutically acceptable salt thereof; may be included as an active ingredient.

In the present invention, "perphenazine" is a mental stabilizer and belongs to a dopamine 3 receptor anatagonist. The perphenazine is represented by the structure of Formula 1 below, and the compound name is 2-chloro-10-{3-[1-(2-hydroxyethyl)-4-piperazinyl]propyl}phenothiazine (2- chloro-10-{3-[1-(2-hydroxyethyl)-4-piperazinyl]propyl}phenothiazine). The perphenazine is commercially available from Schering Co. under the trade name Trilafon®.

[Formula 1]

In the present invention, the biguanide-based compound is a biguanide-based diabetes treatment agent, and in the present invention, specific examples thereof include metformin, phenformin, buformin, or N-(N-( 4-(trifluoromethoxy)phenyl)carbamimidamide, "IM156" ), but may be included without limitation as long as it is a biguanide-based compound that induces a nutritional deficiency-like state by interfering with the generation of energy in cells.

In the present invention, the glucose uptake inhibitor is 2-deoxy-D-glucose (2-deoxy-D-glucose), 3-bromopyruvate (3-bromopyruvate), 3-bromo-2- Oxopropionate-1-propyl ester (3-bromo-2-oxopropionate-1-propyl ester), 5-thioglucose (5-thioglucose) or dichloroacetic acid (dichloroacetic acid), etc. may be, but glucose metabolism in the body As long as it is an inhibitory component, it may be included without limitation.

In the present invention, each of the perphenazine, the biguanide-based compound and the glucose absorption inhibitor may include a pharmaceutically acceptable salt form. Pharmaceutically acceptable salts should have low toxicity to the human body and should not adversely affect the biological activity and physicochemical properties of the parent compound. The pharmaceutically acceptable salt may include, but is not limited to, a pharmaceutically acceptable free acid and an acid addition salt of the perphenazine, the biguanide-based compound, or the glucose absorption inhibitor.

Preferred salt forms of the compounds according to the invention include salts with inorganic or organic acids. In this case, the inorganic acid may be hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, hydrobromic acid, and the like. In addition, organic acids include acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, citric acid, gluconic acid, tartaric acid, salicylic acid, malic acid, Oxalic acid, benzoic acid, embonic acid, aspartic acid, glutamic acid and the like can be used. Organic bases that can be used in the preparation of the organic base addition salt are tris(hydroxymethyl)methylamine, dicyclohexylamine, and the like. Amino acids that can be used to prepare amino acid addition salts are natural amino acids such as alanine and glycine. It will be apparent to those skilled in the art that other acids or bases other than the inorganic acids, organic acids, organic bases and amino acids exemplified above may be used.

In the present invention, the salt form may be prepared by a conventional method. For example, the above-described perphenazine, biguanide-based compound, or glucose absorption inhibitor compound is dissolved in a water-miscible solvent such as methanol, ethanol, acetone, and 1,4-dioxane to form a free acid or a free base. It can be prepared by crystallization after addition.

When two or more compounds (or salts thereof) are simultaneously included in the pharmaceutical composition of the present invention, any two compounds are 1:0.001 to 1:1000, preferably 1:0.01 to 1:100, more preferably 1 It may be used in a molar concentration ratio of :0.1 to 1:10, but is not limited thereto.

The pharmaceutical composition of the present invention can effectively improve or treat cancer by specifically killing cancer cells of origin, and furthermore, it can prevent the onset of cancer itself or prevent cancer recurrence.

In the present invention, the "cancer" refers to or refers to a physiological condition typically characterized by uncontrolled cell growth, and depending on the site of occurrence, brain cancer, ovarian cancer, colorectal cancer, pancreatic cancer, stomach cancer, liver cancer, breast cancer, cervical cancer, Thyroid cancer, parathyroid cancer, lung cancer, non-small cell lung cancer, prostate cancer, gallbladder cancer, biliary tract cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, blood cancer, bladder cancer, kidney cancer, melanoma, colon cancer, bone cancer, skin cancer, head cancer, uterine cancer, Rectal cancer, perianal cancer, fallopian tube carcinoma, endometrial carcinoma, vaginal cancer, vulvar carcinoma, esophageal cancer, small intestine cancer, endocrine adenocarcinoma, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, ureter cancer, renal cell carcinoma, renal pelvic carcinoma, central It may be a CNS central nervoussystem tumor, a primary CNS lymphoma or a spinal cord tumor, preferably a brain cancer, more preferably a glioma or glioblastoma, but is not limited thereto.

In the present invention, the "cell of origin of cancer" refers to a cell of origin having a mutation causing cancer, and for the purpose of the present invention, the cell of origin of cancer may be a cell of origin of brain cancer.

In the present invention, the "cell of origin of brain cancer" may be a cell of the subventricular region or a cell derived therefrom, and may be a cell that has migrated from the subventricular region, preferably, a subventricular region astrocyte versus (astrocytic ribbon) cell or its It may be a cell-derived cell, more preferably, astrocyte-like neural stem cells (astrocyte-like neural stem cells) or a cell derived from astrocytes in the subventricular region.

In the present invention, the "subventricular zone" is a region located on the lateral wall of the lateral ventricle and almost in contact with the ventricle layer, and proliferating cells are concentrated in the subventricular region as well as Rather, it is characterized by being composed of various types of neuronal cells in various stages of maturation.

More specifically, in the present invention, the brain cancer-origin cell may share at least one mutation of TERT 1,295,228 C>T(C228T) and TERT 1,295,250 C>T(C250T) with the brain cancer cell, and measured in the brain cancer-origin cell The expression level (frequency of the variant allele) of at least one mutation of TERT 1,295,228 C>T(C228T) and TERT 1,295,250 C>T(C250T) was measured in the brain cancer cells, wherein the TERT 1,295,228 C>T(C228T) and The expression level (frequency of the variant allele) of at least one mutation of TERT 1,295,250 C>T(C250T) may be lower.

In addition, in the present invention, the brain cancer-derived cells are from the group consisting of brain cancer cells and EGFR (Epidermal growth factor receptor) mutation, TP53 (Tumor protein p53) mutation, PTEN (Phosphatase and tensin homolog) mutation, and Rb1 (Retinoblastoma 1) mutation. may share at least one or more selected mutations, and the frequency or copy number variation of the variant allele of the mutation measured in the cell of brain cancer origin is less than the frequency or copy number variation of the variant allele measured in the brain cancer cell. can

The pharmaceutical composition of the present invention can further enhance the anticancer effect by further including a generally used anticancer agent. Here, the anticancer agent includes nitrogen mustard, imatinib, oxaliplatin, rituximab, erlotinib, neratinib, lapatinib, gefitinib, vandetanib, nirotinib, semasanib, bosutinib, axitinib, masiti nib, cediranib, restaurtinib, trastuzumab, gefitinib, bortezomib, sunitinib, pazopanib, toceranib, nintedanib, regorafenib, semaxanib, tivozanib, ponatinib , caboxantinib carboplatin, sorafenib, lenvatinib, bevacizumab, cisplatin, cetuximab, viscumalbum, asparaginase, tretinoin, hydroxycarbamide, dasatinib, estramustine, gemtuzumab Ozogamycin, ibritumomab tuccetan, heptaplatin, methylaminolevulinic acid, amsacrine, alemtuzumab, procarbazine, alprostadil, holmium chitosan nitrate, gemcitabine, doxyfluridine, pemetrec ced, tegafur, capecitabine, gimeracin, oteracil, azacitidine, methotrexate, uracil, cytarabine, 5-fluorouracil, fludagabine, enocitabine, flutamide, kefecitabine, Decitabine, mercaptopurine, thioguanine, cladribine, carmopher, raltitrexed, docetaxel, paclitaxel, irinotecan, belotecan, topotecan, vinorelbine, etoposide, vincristine, vinblastine, teniposide , doxorubicin, idarubicin, epirubicin, mitoxantrone, mitomycin, bleromycin, daunorubicin, dactinomycin, pyrarubicin, aclarubicin, pepromycin, temsirolimus, temozolomide , busulfan, ifosfamide, cyclophosphamide, melparan, altretmine, dacarbazine, thiotepa, nimustine, chlorambucil, mitolactol, leucovorin, tretonin, exemestane, aminoglute Simid, anagrelide, olaparib, nabelbine, fadrazole, tamoxifen, toremifene, testolactone, anastrozole, letrozole, vorozole, bicalutamide, lomustine, vorinostat, entinostat And it may be at least one selected from the group consisting of carmustine, but is not limited thereto.

In the present invention, "prevention" may include, without limitation, any action that blocks cancer symptoms or suppresses or delays cancer symptoms using the pharmaceutical composition of the present invention.

In the present invention, the pharmaceutical composition may be characterized in the form of capsules, tablets, granules, injections, ointments, powders or drinks, and the pharmaceutical composition may be characterized in that it is targeted to humans.

The pharmaceutical composition of the present invention is not limited thereto, but each can be formulated in the form of oral dosage forms such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories, and sterile injection solutions according to conventional methods. can

The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers may include binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, colorants, fragrances, etc., in the case of oral administration, and in the case of injections, buffers, preservatives, pain relief A topical agent, solubilizer, isotonic agent, stabilizer, etc. can be mixed and used, and in the case of topical administration, a base, excipient, lubricant, preservative, etc. can be used.

The dosage form of the pharmaceutical composition of the present invention can be prepared in various ways by mixing with a pharmaceutically acceptable carrier as described above. For example, in the case of oral administration, it can be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and in the case of injections, it can be prepared in the form of unit dose ampoules or multiple doses. there is. In addition, it can be formulated as a solution, suspension, tablet, capsule, sustained release formulation, and the like.

Meanwhile, examples of suitable carriers, excipients and diluents for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil may be used. In addition, it may further include a filler, an anti-agglomeration agent, a lubricant, a wetting agent, a flavoring agent, an emulsifier, a preservative, and the like.

The route of administration of the pharmaceutical composition according to the present invention is not limited thereto, but oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical , sublingual or rectal. Oral or parenteral administration is preferred.

In the present invention, "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. The pharmaceutical composition of the present invention may also be administered in the form of a suppository for rectal administration.

The pharmaceutical composition of the present invention depends on several factors including the activity of the specific compound used, age, weight, general health, sex, formula, administration time, administration route, excretion rate, drug formulation, and the severity of the specific disease to be prevented or treated. The dosage of the pharmaceutical composition may vary depending on the patient's condition, weight, disease severity, drug form, administration route and period, but may be appropriately selected by those skilled in the art, and 0.0001 to 50 mg/day kg or 0.001 to 50 mg/kg. Administration may be administered once a day, or may be administered in several divided doses. The above dosage does not limit the scope of the present invention in any way. The pharmaceutical composition according to the present invention may be formulated as pills, dragees, capsules, solutions, gels, syrups, slurries, and suspensions.

In another embodiment of the present invention, to a subject in need of administration, (1) perphenazine or a pharmaceutically acceptable salt thereof; and (2) any one of a biguanide-based compound and a glucose uptake inhibitor; Or a pharmaceutically acceptable salt thereof; relates to a method for killing cells of origin, comprising administering a pharmaceutically effective amount.

In another embodiment of the present invention, to a subject in need of administration, (1) perphenazine or a pharmaceutically acceptable salt thereof; and (2) any one of a biguanide-based compound and a glucose uptake inhibitor; Or a pharmaceutically acceptable salt thereof; relates to a method for preventing or treating cancer comprising administering a pharmaceutically effective amount.

In the method for killing cells of origin of cancer and method for preventing or treating cancer of the present invention, perphenazine, biguanide-based compounds, glucose uptake inhibitors, cancer or cell origin of cancer, etc. It is the same as described in the composition for killing and the composition for preventing, improving or treating cancer, and is omitted to avoid excessive complexity of the present specification.

In the present invention, "administration" means providing a given compound of the present invention to a subject by any suitable method.

In the present invention, the "subject" in need of the administration may include both mammals and non-mammals. Here, examples of such mammals include humans, non-human primates such as chimpanzees, other apes or monkey species; livestock animals such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs or cats; laboratory animals such as rodents such as rats, mice or guinea pigs, but are not limited thereto. In addition, examples of the non-mammal in the present invention may include, but are not limited to, birds or fish.

The formulation of the compound administered as described above in the present invention is not particularly limited, and may be administered as a solid formulation, a liquid formulation, or an aerosol formulation for inhalation, and a liquid formulation for oral or parenteral administration immediately before use. It may be administered in a solid form preparation intended to be converted into However, the present invention is not limited thereto.

In addition, during the administration in the present invention, a pharmaceutically acceptable carrier may be additionally administered together with the compound of the present invention. Here, the pharmaceutically acceptable carrier may include a binder, a lubricant, a disintegrant, an excipient, a solubilizer, a dispersing agent, a stabilizer, a suspending agent, a pigment, a flavoring agent, etc., in the case of oral administration, and in the case of an injection, a buffer, Preservatives, analgesics, solubilizers, isotonic agents, stabilizers, etc. can be mixed and used. For topical administration, bases, excipients, lubricants, preservatives, etc. can be used. The formulation of the compound of the present invention can be prepared in various ways by mixing with a pharmaceutically acceptable carrier as described above. For example, in the case of oral administration, it can be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and in the case of injections, it can be prepared in the form of unit dose ampoules or multiple doses. there is. In addition, it can be formulated as a solution, suspension, tablet, capsule, sustained release formulation, and the like.

Meanwhile, examples of suitable carriers, excipients and diluents for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose , methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil may be used. In addition, it may further include a filler, an anti-agglomeration agent, a lubricant, a wetting agent, a flavoring agent, an emulsifier, a preservative, and the like.

Routes of administration of the compounds according to the present invention include, but are not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual or work. Oral or parenteral administration is preferred.

In the present invention, "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. The pharmaceutical composition of the present invention may also be administered in the form of a suppository for rectal administration.

As used herein, a "pharmaceutically effective amount" refers to an amount sufficient of an agent to provide a desired biological result. The result may be reduction and/or alleviation of the signs, symptoms or causes of a disease, or any other desirable change in the biological system. For example, an “effective amount” for therapeutic use is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease. An appropriate “effective” amount in any individual case can be determined by one of ordinary skill in the art using routine experimentation. Accordingly, the expression "effective amount" generally refers to the amount in which the active substance has a therapeutic effect. In the case of the present invention, the active substance is an agent for inducing apoptosis of cells of cancer origin and preventing, ameliorating or treating cancer.

The compound of the present invention may vary depending on several factors including the activity of the specific compound used, age, weight, general health, sex, diet, administration time, administration route, excretion rate, drug formulation, and the severity of the specific disease to be prevented or treated. The dosage of the compound may vary depending on the patient's condition, body weight, disease severity, drug form, administration route and duration, but may be appropriately selected by those skilled in the art, and may be 0.0001 to 100 mg/kg or 0.001 to 0.001 to 100 mg/kg per day. It can be administered at 100 mg/kg. Administration may be administered once a day, or may be administered in several divided doses. The above dosage does not limit the scope of the present invention in any way. The compound according to the present invention can be formulated as pills, dragees, capsules, solutions, gels, syrups, slurries, and suspensions.

The compounds of the present invention may be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers.

In addition, the compound of the present invention may be used in combination with other anticancer agents, wherein the anticancer agents include nitrogen mustard, imatinib, oxaliplatin, rituximab, erlotinib, neratinib, lapatinib, gefitinib, vande tanib, nirotinib, semasanib, bosutinib, axitinib, cediranib, restaurtinib, trastuzumab, gefitinib, bortezomib, sunitinib, carboplatin, sorafenib, bevacizumab, Cisplatin, cetuximab, viscumalbum, asparaginase, tretinoin, hydroxycarbamide, dasatinib, estramustine, gemtuzumab ozogamicin, ibritumomab tucetan, heptaplatin, methylaminolevulinic acid , amsacrine, alemtuzumab, procarbazine, alprostadil, holmium nitrate chitosan, gemcitabine, doxyfluridine, pemetrexed, tegafur, capecitabine, gimeracin, oteracil, azacit Dean, methotrexate, uracil, cytarabine, fluorouracil, fludabine, enocitabine, flutamide, kepecitabine, decitabine, mercaptopurine, thioguanine, cladribine, carmofer, raltitrexed, docetaxel, paclitaxel, irinotecan, belotecan, topotecan, vinorelbine, etoposide, vincristine, vinblastine, teniposide, doxorubicin, idarubicin, epirubicin, mitoxantrone, mitomycin, bleromycin , daunorubicin, dactinomycin, pyrarubicin, aclarubicin, pepromycin, temsirolimus, temozolomide, busulfan, ifosfamide, cyclophosphamide, melparan, altretmine, daca Vazine, thiotepa, nimustine, chlorambucil, mitolactol, leucovorin, tretonin, exemestane, aminoglutethimide, anagrelide, olaparib, nabelbine, fadrazole, tamoxifen, toremi At least one selected from the group consisting of phen, testolactone, anastrozole, letrozole, vorozol, bicalutamide, lomustine, vorinostat, entinostat, phenformin, metformin, thalazoparib and carmustine can be used, but is not limited thereto.

The pharmaceutical composition of the present invention can effectively improve or treat cancer by specifically killing cells of origin, and furthermore, it can prevent the onset of cancer itself or prevent recurrence of cancer.

1 is a change in cell viability after treatment with perphenazine (P) (2.5 uM, 5 uM) and IM156 (2.5 uM) in combination with subventricular region cells (SVZ), which are cells of glioblastoma origin in Example 1; is shown graphically.

2 is a change in cell viability after treatment with perphenazine (P) (2.5 uM, 5 uM) and IM156 (2.5 uM) in combination with cells (mSVZ) that migrated from the subventricular region to the caudal cortex in Example 1; is shown graphically.

3 shows intracellular ATP levels after treatment with perphenazine (P) (2.5 uM, 5 uM) and IM156 (2.5 uM) in combination with subventricular region cells (SVZ), which are cells of glioblastoma origin in Example 1; The change is shown graphically.

Figure 4 shows the intracellular ATP level after treatment with perphenazine (P) (2.5 uM, 5 uM) and IM156 (2.5 uM) in combination with cells (mSVZ) that migrated from the subventricular region to the caudal cortex in Example 1. The change is shown graphically.

5 is a dose-response matrix based on the results of a WST assay measuring the change in cell viability after treatment with perphenazine and IM156 at different concentrations in subventricular region cells (SVZ), which are cells of origin of glioblastoma in Example 1; (dose-response matrix) and Bliss synergy score are measured results.

6 is a dose-response matrix based on the results of the WST assay measuring the change in cell viability after treatment with perphenazine and IM156 by concentration in cells (mSVZ) that migrated from the subventricular region to the caudal cortex in Example 1; (dose-response matrix) and Bliss synergy score are measured results.

7 is a dose-response based on the experimental results of measuring changes in intracellular ATP levels after treatment with perphenazine and IM156 at different concentrations in subventricular region cells (SVZ), which are cells of origin of glioblastoma in Example 1; It shows the results of measuring the dose-response matrix and the Bliss synergy score.

8 is a dose-response based on the experimental results of measuring changes in intracellular ATP levels after treatment with perphenazine and IM156 by concentration in cells (mSVZ) that migrated from the subventricular region to the caudal cortex in Example 1; It shows the results of measuring the dose-response matrix and the Bliss synergy score.

9 shows the shape of sphere cells after treatment with perphenazine (P) (3.5 uM) and IM156 (2.5 uM) alone or in combination with subventricular region cells (SVZ), which are cells of glioblastoma origin in Example 2; The picture was taken with a phase contrast microscope.

Figure 10 shows the shape of sphere cells after treatment with perphenazine (P) (3.5 uM) and IM156 (2.5 uM) alone or in combination with cells (mSVZ) that migrated from the subventricular region to the caudal cortex in Example 2; The picture was taken with a phase contrast microscope.

11 shows the infiltration area of sphere cells after treatment with perphenazine (P) (3.5 uM) and IM156 (2.5 uM) alone or in combination with cells (mSVZ) that migrated from the subventricular region to the caudal cortex in Example 2; The results of the measurements are presented in a graph.

12 shows the infiltration area of sphere cells after treatment with perphenazine (P) (3.5 uM) and IM156 (2.5 uM) alone or in combination with cells (mSVZ) that migrated from the subventricular region to the caudal cortex in Example 2; The results of the measurements are presented in a graph.

13 shows spear cells of subventricular region cells (SVZ), which are cells of origin of glioblastoma in Example 3, after treatment with perphenazine (P) (2.5 uM) and IM156 (2.5 uM) alone or in combination. The picture shows the shape of the image taken with a phase-contrast microscope.

14 is a spear cell after treatment with perphenazine (P) (2.5 uM) and IM156 (2.5 uM) alone or in combination with spear cells of cells (mSVZ) that migrated from the subventricular region to the caudal cortex in Example 3; The picture shows the shape of the image taken with a phase-contrast microscope.

FIG. 15 shows spear cells of subventricular region cells (SVZ), which are cells of glioblastoma origin, treated with perphenazine (PER) (2.5 uM) and IM156 (2.5 uM) alone or in combination in Example 3; The result of measuring the number of wells containing

16 is a spear cell after treatment with perphenazine (PER) (2.5 uM) and IM156 (2.5 uM) alone or in combination with spear cells of cells (mSVZ) that migrated from the subventricular region to the caudal cortex in Example 3; The result of measuring the number of wells containing

17 is a spear cell after treatment with perphenazine (PER) (2.5 uM) and IM156 (2.5 uM) alone or in combination with sphere cells of subventricular region cells (SVZ), which are cells of glioblastoma origin in Example 3; The result of measuring the radius of is shown as a graph.

18 is a spear cell after treatment with perphenazine (PER) (2.5 uM) and IM156 (2.5 uM) alone or in combination with spear cells of cells (mSVZ) migrated from the subventricular region to the caudal cortex in Example 3; The result of measuring the radius of is shown as a graph.

19 shows cells after treatment with perphenazine (P) (2.5 uM, 5 uM) and metformin (Met) (0.5 mM) in combination with subventricular region cells (SVZ), which are cells of glioblastoma origin in Example 4; The change in survival rate is shown graphically.

20 shows cells (mSVZ) migrating from the subventricular region to the caudal cortex in Example 4 after treatment with perphenazine (P) (2.5 uM, 5 uM) and metformin (Met) (0.5 mM) in combination; The change in survival rate is shown graphically.

Figure 21 shows the cells (mSVZ) that migrated from the subventricular region to the caudal cortex in Example 4 after treatment with perphenazine (P) (2.5 uM, 5 uM) and metformin (Met) (1 mM) in combination. A graph showing the change in my ATP level.

22 is a dose-response matrix based on the results of a WST assay measuring changes in cell viability after treatment with perphenazine and metformin by concentration in subventricular region cells (SVZ), which are cells of origin of glioblastoma in Example 4; (dose-response matrix) and Bliss synergy score are measured results.

23 is a dose-response matrix based on the results of a WST assay measuring changes in cell viability after treatment with perphenazine and metformin by concentration in cells (mSVZ) that migrated from the subventricular region to the caudal cortex in Example 4; (dose-response matrix) and Bliss synergy score are measured results.

24 is a dose-response based on the experimental results of measuring changes in intracellular ATP levels after treatment with perphenazine and metformin by concentration in cells (mSVZ) that migrated from the subventricular region to the caudal cortex in Example 4; It shows the results of measuring the dose-response matrix and the Bliss synergy score.

FIG. 25 shows that cells (mSVZ) migrated from the subventricular region to the tail cortex in Example 5 were treated with perphenazine (P) (2.5 uM, 5 uM) and phenformin (Phen) (25 uM) in combination. The change in cell viability is shown graphically.

26 is a dose-response based on the results of a WST assay measuring the change in cell viability after treating subventricular region cells (SVZ), which are cells of glioblastoma origin, in Example 5 in combination with perphenazine and phenformin by concentration. It shows the results of measuring the dose-response matrix and the Bliss synergy score.

27 is a dose-response based on the results of a WST assay measuring changes in cell viability after treatment with perphenazine and phenformin by concentration in cells (mSVZ) that migrated from the subventricular region to the tail cortex in Example 5; It shows the results of measuring the dose-response matrix and the Bliss synergy score.

28 shows perphenazine (P) (2.5 uM, 5 uM) and 2-deoxy-D-glucose (2DG) (0.5 mM) in subventricular zone cells (SVZ), which are cells of glioblastoma origin in Example 6; It is a graph showing the change in cell viability after treatment in combination with

29 shows perphenazine (P) (2.5 uM, 5 uM) and 2-deoxy-D-glucose (2DG) (1 mM) in subventricular zone cells (SVZ), which are cells of glioblastoma origin in Example 6; It is a graph showing the change in the intracellular ATP level after treatment in combination with

In one embodiment of the present invention, (1) perphenazine (perphenazine) or a pharmaceutically acceptable salt thereof; and (2) any one of a biguanide-based compound and a glucose uptake inhibitor; Or a pharmaceutically acceptable salt thereof; provides a pharmaceutical composition for killing cells of origin including cancer as an active ingredient.

In another embodiment of the present invention, (1) perphenazine or a pharmaceutically acceptable salt thereof; and (2) any one of a biguanide-based compound and a glucose uptake inhibitor; Or a pharmaceutically acceptable salt thereof; provides a pharmaceutical composition for the prevention or treatment of cancer comprising as an active ingredient.

In another embodiment of the present invention, to a subject in need of administration, (1) perphenazine or a pharmaceutically acceptable salt thereof; and (2) any one of a biguanide-based compound and a glucose uptake inhibitor; Or a pharmaceutically acceptable salt thereof; provides a method of killing cells of origin, comprising administering a pharmaceutically effective amount.

In another embodiment of the present invention, to a subject in need of administration, (1) perphenazine or a pharmaceutically acceptable salt thereof; and (2) any one of a biguanide-based compound and a glucose uptake inhibitor; Or a pharmaceutically acceptable salt thereof; provides a method for preventing or treating cancer comprising administering a pharmaceutically effective amount.

Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .

Example

[Preparation Example 1] Preparation of cancer-origin cells

A mouse glioblastoma model was constructed in the same manner as in Korean Patent Publication No. 10-2019-0095074. Specifically, LoxP-Stop-LoxP EGFRviii mice (FVB strain) and LoxP-Stop-LoxP-tdTomato mice (C57BL/6) obtained by crossing LoxP-Stop-LoxP EGFRvii f/+; LoxP-Stop-LoxP tdTomato f/ + In mice, using CRISPR-Cas9 technology, protein 53 (P53), phosphatase and tensin homolog (PTEN) genes were selectively removed or mutated to model a mouse glioblastoma was built. After 14 weeks of mouse model construction, mice were euthanized and brains were removed. The subventricular zone (SVZ) corresponding to the origin of glioblastoma and the caudal cortex region where cells migrated from the subventricular region were separated from the extracted mouse brain. MEM/nutrient mixture F-12 (DMEM/F-12; Mediatech) was added to the subventricular zone (SVZ) tissue and the caudal cortex tissue where cells migrated from the subventricular zone, respectively, and separated using a scalpel made it Then, the separated sample was passed through a 100-um nylon mesh cell strainer (BD Falcon, Franklin Lakes, NJ, USA). Cell suspensions were washed twice in DEME/F-12, 1 x B27 complement (Invitrogen, San Diego, CA, USA), 20 ng/ml of basic fibroblast growth factor (bFGF; Sigma, St. Louis, MO, USA), 20 ng/ml of epidermal growth factor (EGF; Sigma), and 50 U/ml of penicillin and 50 mg/ml of streptomycin (DMEM/F-12).

[Example 1] Synergistic effect of perphenazine and IM156 in killing cells of cancer origin

1. WST Assay

10,000 cells/well each inoculated into a 96-well plate with subventricular zone cells (SVZ), which are cells of glioblastoma origin, and cells (migrated subventricular zone, mSVZ) that migrated from the subventricular zone to the tail cortex, After culturing for 24 hours, a medium treated with perphenazine (2.5 uM, 5 uM) and IM156 (2.5 uM) was added. Then, incubate for 72 hours, add WST reagent (D-Plus ^TM CCK cell viability assay kit, Dongin LS), incubate for 2 more hours, measure absorbance at 450 nm, calculate % compared to control, and process each group Cell viability was measured according to The results are shown in FIGS. 1 and 2 .

As shown in FIGS. 1 and 2 , it was confirmed that cell viability was significantly reduced when perphenazine and IM156 were administered in combination with subventricular region cells, which are carcinogenic origin cells of glioblastoma, and cells migrated therefrom.

2. ATP activity change experiment

Subventricular region cells (SVZ), which are cells of glioblastoma origin, and cells (mSVZ) migrated from the subventricular region to the tail cortex (mSVZ) were inoculated into a 96-well plate at 10,000 cells/well, and cultured for 24 hours followed by Perpena A medium treated with gin (2.5 uM, 5 uM) and IM156 (2.5 uM) was added. Then, after 72 hours of incubation, as soon as CellTiter-Glo luminescent cell viability assay kit (Promega) was added, fluorescence was measured to measure ATP activity (%) compared to the control. The results are shown in FIGS. 3 and 4 .

As shown in FIGS. 3 and 4 , when perphenazine and IM156 were administered in combination to the subventricular region cells, which are carcinogenic origin cells of glioblastoma, and cells migrated therefrom, it was confirmed that the intracellular ATP activity was significantly reduced.

3. Bliss synergy score analysis

SynergyFinder based on the results of the WST assay experiment and ATP activity change experiment for subventricular region cells (SVZ) and cells migrated from the subventricular region (mSVZ), which are cells of glioblastoma origin, performed in 1. Using the Bliss model algorithm of the program, the combined effect of two drugs perphenazine and IM156 on the apoptosis of cancer-derived cells was predicted, and the results are shown in Table 1 and FIGS. 5 to 8 below. However, the following Bliss synergy score is performed based on the reference (Aleksandr et al. SynergyFinder: a web application for analyzing drug combination dose-response matrix data. Bioinformatics, 33, 15, 2017, 2413-2415) became

pharmaceutical combination	Bliss Synergy Score (based on WST assay results)		Bliss Synergy Score (Based on ATP activity test results)
	SVZ	mSVZ	SVZ	mSVZ
Perphenazine+IM156	8.971	10.684	13.963	13.827

The greater the difference between the value predicted by the Bliss model and the actual value by applying the concentration combination of perphenazine and IM156 to each drug as 4x4, it has a value higher than 0. As shown in Table 1 and FIGS. 5 to 8, in the case of the combination of perphenazine and IM156, a red color, which is a positive value as a whole, was displayed at each concentration. A synergistic effect was given to the death of cancer-origin cells according to the combination of the two drugs. was able to confirm More specifically, it was found that the survival inhibition rate of each cell was approximately 80% at the highest treatment concentrations of perphenazine and IM156, and perphenazine 2.5 uM and IM156 2.5 uM were found at the highest synergistic concentrations.

[Example 2] Inhibitory effect of perphenazine and IM156 on cell invasion of cancer origin

Through 3D invasion assay, subventricular region cells (SVZ), which are cells of origin of glioblastoma, and sphere cells of cells (mSVZ) migrated from the subventricular region to the tail cortex (mSVZ) were transplanted into the type I collagen matrix. Phenazine (3.5 uM) and IM156 (2.5 uM) were treated with phenazine (3.5 uM) and IM156 (2.5 uM) individually or in combination. At 72 hours, the shape of the sphere cells was photographed with a phase-contrast microscope, and the results are shown in FIGS. 9 and 10, and the sphere cells after each treatment The infiltration area was measured and the results are shown in graphs in FIGS. 11 and 12 .

As shown in FIGS. 9 to 12, when perphenazine and IM156 were administered in combination to the subventricular region cells, which are cells of carcinogenic origin of glioblastoma, and cells migrated therefrom, the cell invasiveness was significantly lower than when they were administered alone. could check

[Example 3] Inhibitory effect of perphenazine and IM156 on tumor cell formation ability of cancer-origin cells

Single cells of subventricular zone cells (SVZ), which are cells of glioblastoma origin, and cells migrating from the subventricular zone to the caudal cortex (mSVZ), were planted in each well of 5 perpenazine (2.5 uM) and IM156 ( 2.5 uM) respectively or in combination, the effect on the formation of sphere cells was observed. After 10 to 11 days, it was photographed with a phase contrast microscope and shown in FIGS. 13 and 14. The number of wells containing spear cells was measured and the results are shown in FIGS. 15 and 16, and the radius of the sphere cells was measured and the results are shown. 17 and 18 show.

As shown in FIGS. 13 to 18 , when perphenazine and IM156 were administered in combination with subventricular region cells, which are cells of carcinogenic origin of glioblastoma, and cells migrated therefrom, the frequency or size of sphere cell formation compared to when they were administered alone. was found to be significantly reduced.

[Example 4] Synergistic effect of perphenazine and metformin on apoptosis of cancer-origin cells

1. WST Assay

The experiment was performed in the same manner as in the WST assay of Example 1, except that the treated material was treated with perphenazine (2.5 uM, 5 uM) and metformin (0.5 mM) in combination. Changes in cell viability according to each treatment were measured, and the results are shown in FIGS. 19 and 20 .

As shown in FIGS. 19 and 20 , it was confirmed that the cell viability was significantly reduced when perphenazine and metformin were administered in combination to the subventricular region cells, which are cells of carcinogenic origin of glioblastoma, and cells migrated therefrom.

2. ATP activity change experiment

The experiment was performed in the same manner as the ATP activity change experiment of Example 1, except that the subventricular region cells, which are cells of origin of glioblastoma, were carried out for cells (mSVZ) migrated to the tail cortex, and the treated material was treated with perphenazine ( 2.5 uM, 5 uM) and metformin (1 mM) were used in combination. The ATP activity (%) compared to the control group according to each treatment was measured, and the results are shown in FIG. 21 .

As shown in FIG. 21 , when perphenazine and metformin were administered in combination to cells migrated from the subventricular region, which is a carcinogenic origin of glioblastoma, it was confirmed that intracellular ATP activity was significantly reduced.

3. Bliss synergy score analysis

Based on the results of the WST assay experiment of perphenazine and metformin on the subventricular region cells (SVZ) and the cells migrating from the subventricular region (mSVZ) in the same manner as in Example 1, and the ATP activity change experiment results of these two drugs The combined effect on the death of cancer-origin cells was predicted and the results are shown in Table 2 and FIGS. 22 to 24 below.

pharmaceutical combination	Bliss Synergy Score (based on WST assay results)		Bliss Synergy Score (Based on ATP activity test results)
	SVZ	mSVZ	SVZ	mSVZ
Perphenazine + Metformin	13.658	10.092	0.351	13.508

As shown in Table 2 and FIGS. 22 to 24, in the case of the combination of perphenazine and metformin, a red color, which is a positive value as a whole, was displayed at each concentration. The combination of the two drugs showed a synergistic effect on the death of cells of cancer origin. could be confirmed to have been granted.

[Example 5] Synergistic effect of perphenazine and phenformin in apoptosis of cancer-origin cells

1. WST Assay

The experiment was performed in the same manner as in the WST assay of Example 1, but the treatment material was treated with perphenazine (5 uM) and phenformin (50 uM) in combination, and then the change in cell viability was measured, and the results are shown in FIG. 25 shown in

As shown in FIG. 25 , it was confirmed that the cell viability was significantly reduced when perphenazine and phenformin were administered in combination to the subventricular region cells, which are carcinogenic origin cells of glioblastoma, and cells migrated therefrom.

2. Bliss synergy score analysis

Based on the WST assay results of perphenazine and phenformin for subventricular region cells (SVZ) and cells migrated from the subventricular region (mSVZ) in the same manner as in Example 1, the two drugs were used to kill cancer-origin cells. The combined effect was predicted and the results are shown in Table 3 and FIGS. 26 and 27 below.

pharmaceutical combination	Bliss Synergy Score (based on WST assay results)
	SVZ	mSVZ
perphenazine + phenformin	3.53	9.63

As shown in Table 3 and FIGS. 26 and 27, in the case of the combination of perphenazine and phenformin, a red color, which is an overall positive value, was exhibited at each concentration. The combination of the two drugs showed a synergistic effect on the death of cells of cancer origin. could be confirmed to have been granted.

[Example 6] Synergistic effect of perphenazine and 2-deoxy-D-glucose in killing cells of cancer origin

1. WST Assay

The experiment was performed in the same manner as in the WST assay of Example 1, except that the subventricular region cells (SVZ), which are cells of origin of glioblastoma, were treated with perphenazine (2.5 uM, 5 uM) and 2 After treatment with -deoxy-D-glucose (0.5 mM), the change in cell viability was measured, and the results are shown in FIG. 28 .

As shown in FIG. 28 , it was confirmed that cell viability was significantly reduced when perphenazine and 2-deoxy-D-glucose were administered in combination to subventricular region cells, which are carcinogenic origin cells of glioblastoma.

2. ATP activity change experiment

The experiment was performed in the same manner as the ATP activity change experiment of Example 1, except that the subventricular region cells, which are cells of origin of glioblastoma, were performed on cells (mSVZ) migrated to the tail cortex, and perphenazine was used as the treatment material. (2.5 uM, 5 uM) and 2-deoxy-D-glucose (1 mM) were used in combination. The ATP activity (%) compared to the control group according to each treatment was measured, and the results are shown in FIG. 29 .

As shown in FIG. 29 , when perphenazine and 2-deoxy-D-glucose were administered in combination to subventricular region cells, which are cells of carcinogenic origin of glioblastoma, it was confirmed that intracellular ATP activity was significantly reduced.

3. Bliss synergy score analysis

Based on the results of the WST assay experiment and ATP activity change experiment results of the combination of perphenazine and 2-deoxy-D-glucose for cells (mSVZ) migrated from the subventricular region in the same manner as in Example 1, the two drugs were The combined effect on the apoptosis of cancer-derived cells was predicted and the results are shown in Table 4 below.

pharmaceutical combination	Bliss Synergy Score (based on WST assay results)	Bliss Synergy Score (Based on ATP activity test results)
	SVZ	SVZ
Perphenazine+2-DG	1.247	9.658

As shown in Table 4 above, in the combination of perphenazine and 2-deoxy-D-glucose, the Bliss synergy score all had a value greater than 0, and in particular, the ATP activity test result showed 9.658, and the combination was of cancer origin. It was confirmed that a synergistic effect was imparted to cell death.

Although the embodiments of the present invention have been described in detail above, the scope of the present invention is not limited thereto, and various modifications and variations are possible within the scope without departing from the technical spirit of the present invention described in the claims. It will be apparent to those of ordinary skill in the art.

When the composition of the present invention is used, it is possible to effectively improve or treat cancer by specifically killing cells of origin of cancer, and furthermore, it is possible to prevent the onset of cancer itself or to prevent recurrence of cancer.

Claims (13)

1. (1) perphenazine or a pharmaceutically acceptable salt thereof; and

   (2) any one of a biguanide-based compound and a glucose uptake inhibitor; Or a pharmaceutically acceptable salt thereof; a pharmaceutical composition for killing cells of origin of cancer comprising as an active ingredient.
2. According to claim 1,

   The biguanide-based compound is metformin, phenformin, buformin, and N-(N-(4-(trifluoromethoxy)phenyl)carbamaimidoyl)pyrrolidine-1 -Carboximidamide (N-(N-(4-(trifluoromethoxy)phenyl)carbamimidoyl)pyrrolidine-1-carboximidamide) at least one selected from the group consisting of, a pharmaceutical composition.
3. According to claim 1,

   The glucose absorption inhibitor is 2-deoxy-D-glucose, 3-bromopyruvate, 3-bromo-2-oxopropionate-1-propyl Ester (3-bromo-2-oxopropionate-1-propyl ester), 5-thioglucose (5-thioglucose) and dichloroacetic acid (dichloroacetic acid) at least one selected from the group consisting of, a pharmaceutical composition.
4. According to claim 1,

   The cancers include brain cancer, ovarian cancer, colorectal cancer, pancreatic cancer, stomach cancer, liver cancer, breast cancer, cervical cancer, thyroid cancer, parathyroid cancer, lung cancer, non-small cell lung cancer, prostate cancer, gallbladder cancer, biliary tract cancer, non-Hodgkin's lymphoma, Hodgkin's lymphoma, Blood cancer, bladder cancer, kidney cancer, melanoma, colon cancer, bone cancer, skin cancer, head cancer, uterine cancer, rectal cancer, perianal cancer, fallopian tube carcinoma, endometrial carcinoma, vaginal cancer, vulvar carcinoma, esophageal cancer, small intestine cancer, endocrine adenocarcinoma, adrenal cancer , soft tissue sarcoma, urethral cancer, penile cancer, ureteral cancer, renal cell carcinoma, renal pelvic carcinoma, CNS central nervoussystem tumor, primary CNS lymphoma or spinal cord tumor, a pharmaceutical composition.
5. According to claim 1,

   The cell of origin of cancer is a cell of origin of brain cancer, pharmaceutical composition.
6. 6. The method of claim 5,

   The cell of origin of the brain cancer is a subventricular zone (SVZ) cells or cells migrated from the subventricular zone, a pharmaceutical composition.
7. According to claim 1,

   The pharmaceutical composition is for preventing the onset or recurrence of cancer, the pharmaceutical composition.
8. (1) perphenazine or a pharmaceutically acceptable salt thereof; and

   (2) any one of a biguanide-based compound and a glucose uptake inhibitor; Or a pharmaceutically acceptable salt thereof; a pharmaceutical composition for the prevention or treatment of cancer comprising as an active ingredient.
9. 9. The method of claim 8,

   The biguanide-based compound is metformin, phenformin, buformin, and N-(N-(4-(trifluoromethoxy)phenyl)carbamaimidoyl)pyrrolidine-1 -Carboximidamide (N-(N-(4-(trifluoromethoxy)phenyl)carbamimidoyl)pyrrolidine-1-carboximidamide) at least one selected from the group consisting of, a pharmaceutical composition.
10. 9. The method of claim 8,

    The glucose absorption inhibitor is 2-deoxy-D-glucose, 3-bromopyruvate, 3-bromo-2-oxopropionate-1-propyl Ester (3-bromo-2-oxopropionate-1-propyl ester), 5-thioglucose (5-thioglucose) and dichloroacetic acid (dichloroacetic acid) at least one selected from the group consisting of, a pharmaceutical composition.
11. 9. The method of claim 8,

    The cancers include brain cancer, ovarian cancer, colorectal cancer, pancreatic cancer, stomach cancer, liver cancer, breast cancer, cervical cancer, thyroid cancer, parathyroid cancer, lung cancer, non-small cell lung cancer, prostate cancer, gallbladder cancer, biliary tract cancer, non-Hodgkin's lymphoma, Hodgkin's lymphoma, Blood cancer, bladder cancer, kidney cancer, melanoma, colon cancer, bone cancer, skin cancer, head cancer, uterine cancer, rectal cancer, perianal cancer, fallopian tube carcinoma, endometrial carcinoma, vaginal cancer, vulvar carcinoma, esophageal cancer, small intestine cancer, endocrine adenocarcinoma, adrenal cancer , soft tissue sarcoma, urethral cancer, penile cancer, ureteral cancer, renal cell carcinoma, renal pelvic carcinoma, CNS central nervoussystem tumor, primary CNS lymphoma or spinal cord tumor, a pharmaceutical composition.
12. To a subject in need of administration,

    (1) perphenazine or a pharmaceutically acceptable salt thereof; and

    (2) any one of a biguanide-based compound and a glucose uptake inhibitor; Or a pharmaceutically acceptable salt thereof; a method of killing cells of origin of cancer comprising administering a pharmaceutically effective amount.
13. To a subject in need of administration,

    (1) perphenazine or a pharmaceutically acceptable salt thereof; and

    (2) any one of a biguanide-based compound and a glucose uptake inhibitor; Or a pharmaceutically acceptable salt thereof; a method of preventing or treating cancer comprising administering a pharmaceutically effective amount.

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