KR20220034531A - Pharmaceutical composition for the death of cancer origin cell - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for killing cancer origin cells, comprising perphenazine, a biguanide-based compound, and a glucose uptake inhibitor as active ingredients. The pharmaceutical composition of the present invention can effectively alleviate or treat cancer by specifically killing cancer origin cells, and furthermore, prevent the onset of cancer itself or prevent cancer recurrence.

Description

Pharmaceutical composition for the death of cancer origin cell {Pharmaceutical composition for the death of cancer origin cell}

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.

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;

(2) a biguanide-based compound or a pharmaceutically acceptable salt thereof; and

(3) 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 of ordinary skill in the art that other acids or bases may be used in addition to the inorganic acids, organic acids, organic bases and amino acids exemplified above.

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.

In the pharmaceutical composition of the present invention, any two compounds of the perphenazine, the biguanide-based compound and the glucose absorption inhibitor are 1:0.001 to 1:1000, preferably 1:0.01 to 1:100, more preferably It may be used in a molar concentration ratio of 1:0.1 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 brain cancer origin" may be a cell of the subventricular region or a cell derived therefrom, which 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 composition of the present invention can further improve 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.

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 shows perphenazine (P) (10 uM, 25 uM, 50 uM), 2-deoxy-D-glucose (2DG) in subventricular zone cells (SVZ), which are cells of glioblastoma origin in Example 1 ( 1 mM) and metformin (Met) (1 mM) after treatment with a combination of the change in cell viability is shown as a graph.
2 is a WST measurement of changes in cell viability after treatment with perphenazine, 2-deoxy-D-glucose, and metformin at different concentrations in subventricular region cells (SVZ), which are cells of origin of glioblastoma in Example 2; Based on the assay results, a dose-response matrix is shown.
3 is a WST measurement of changes in cell viability after treatment with perphenazine, 2-deoxy-D-glucose, and metformin at different concentrations in subventricular region cells (SVZ), which are cells of origin of glioblastoma in Example 2; It shows the results of measuring the Bliss synergy score based on the assay results.

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, metformin and 2-deoxy-D-glucose in the killing of cancer-origin cells (1)

Subventricular region cells (SVZ), which are cells of origin of glioblastoma, were inoculated at 10,000 cells/well in a 96-well plate, and cultured for 24 hours with perphenazine, metformin and 2-deoxy -D-glucose (2-deoxyglucose) was added to the treated medium by concentration. 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 Cell viability was measured accordingly. The results are shown in FIG. 1 .

As shown in FIG. 1 , compared to the case where metformin and 2-deoxy-D-glucose were treated in combination with subventricular region cells, which are cells of carcinogenic origin of glioblastoma, the cell viability was significantly reduced when treated in combination with perphenazine. could confirm that

[Example 2] Synergistic effect of perphenazine, metformin and 2-deoxy-D-glucose in the killing of cancer-origin cells (2)

Perphenazine using the Bliss model algorithm of the SynergyFinder program based on the results of the WST assay for subventricular region cells (SVZ), which is the cell of origin of glioblastoma, performed in Example 1 above; The combined effects of metformin and 2-deoxy-D-glucose three drugs on apoptosis of cancer-derived cells were predicted, and the results are shown in FIGS. 2 and 3 . 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

By applying the concentration combination of each drug used in combination as 4x4, the greater the difference between the value predicted by the Bliss model and the actual value, the higher the repayment will be than 0. As shown in Figures 2 and 3, in the case of the combination of perphenazine, metformin, and 2-deoxy-D-glucose, a red color, which is generally a + value, was displayed at each concentration, and the Bliss synergy score was calculated as 14.433, It was confirmed that a synergistic effect was imparted to the death of cancer-origin cells according to the combination of these three drugs.

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.

Claims (11)

(1) perphenazine or a pharmaceutically acceptable salt thereof;
(2) a biguanide-based compound or a pharmaceutically acceptable salt thereof; and
(3) 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. 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. 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. 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. According to claim 1,
The cell of origin of cancer is a cell of origin of brain cancer, pharmaceutical composition. 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. According to claim 1,
The pharmaceutical composition is for preventing the onset or recurrence of cancer, the pharmaceutical composition. (1) perphenazine or a pharmaceutically acceptable salt thereof;
(2) a biguanide-based compound or a pharmaceutically acceptable salt thereof; and
(3) A pharmaceutical composition for preventing or treating cancer comprising a glucose uptake inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient. 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. 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. 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.

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