WO2017142348A1 - Composition pharmaceutique pour le traitement d'un cancer, contenant un composé polyphénol utilisé comme principe actif - Google Patents

Composition pharmaceutique pour le traitement d'un cancer, contenant un composé polyphénol utilisé comme principe actif Download PDF

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WO2017142348A1
WO2017142348A1 PCT/KR2017/001783 KR2017001783W WO2017142348A1 WO 2017142348 A1 WO2017142348 A1 WO 2017142348A1 KR 2017001783 W KR2017001783 W KR 2017001783W WO 2017142348 A1 WO2017142348 A1 WO 2017142348A1
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cancer
pharmaceutical composition
cells
stem cells
cell
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PCT/KR2017/001783
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English (en)
Korean (ko)
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정재호
김수열
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연세대학교 산학협력단
국립암센터
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Priority to CN201780013437.0A priority Critical patent/CN108697667A/zh
Priority to US15/999,726 priority patent/US10864178B2/en
Priority to EP17753509.3A priority patent/EP3417853B1/fr
Priority to JP2018536492A priority patent/JP6829723B2/ja
Priority claimed from KR1020170021460A external-priority patent/KR101904893B1/ko
Publication of WO2017142348A1 publication Critical patent/WO2017142348A1/fr
Priority to IL261196A priority patent/IL261196B/en
Priority to HK18116737.4A priority patent/HK1257615A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/11—Aldehydes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37—Coumarins, e.g. psoralen

Definitions

  • the present invention relates to a pharmaceutical composition for treating cancer comprising the polyphenol compound as an active ingredient.
  • Cancer is one of the most common causes of death worldwide. About 10 million new cases occur each year, accounting for about 12% of all deaths, causing the third largest number of deaths. Therefore, while efforts to develop effective anticancer drugs have been continued, most recently developed anticancer drugs target general cancer cells, and are not effective for killing cancer stem cells, which play an important role in treatment resistance and recurrence of cancer patients.
  • the cancer stem cell is a cancer cell having unlimited regenerative capacity similar to a general stem cell, and slowly proliferates differently from a general cancer cell, and has self-renewal or differentiation ability, which is unique to stem cells, and known cancer cells.
  • Gossypol as a polyphenol compound corresponds to a phenol derivative contained in a large amount in a cotton plant.
  • Gosipol has been found to inhibit sperm function in males, and has been developed as a male oral contraceptive pill, but recently it has been known that there is a significant effect on Gosipol's cancer cell growth inhibition (US Patent US6114397).
  • US Patent US6114397 it is difficult to effectively inhibit cancer cell growth by administering Gosipol alone alone.
  • the present invention relates to a pharmaceutical composition for treating cancer and cancer stem cells comprising a polyphenol compound as an active ingredient, wherein the pharmaceutical composition according to the present study contains a large amount of cancer stem cells such as cancer stem cells or low-differentiated cancer. It is very effective in treating cancer tissues and improving the prognosis.
  • polyphenol compounds, biguanide-based compounds, and anticancer agents are used in combination with cancer cells, and thus, the effects of inhibiting cancer cell growth are significantly increased compared to those administered alone, and are expected to be greatly utilized in the field of cancer treatment.
  • the present invention has been made to solve the above problems in the prior art, and relates to a pharmaceutical composition for treating cancer comprising a polyphenol compound as an active ingredient.
  • cancer is characterized by uncontrolled cell growth, and by this abnormal cell growth, a cell mass called a tumor is formed, penetrating into surrounding tissues, and in severe cases, to other organs of the body. It is also said to be transferred. Academics are also called neoplasms. Cancer is a refractory chronic disease that, even if treated with surgery, radiation and chemotherapy, does not cure in many cases, suffers from the patient and ultimately leads to death, and there are many causes of cancer, but internal factors It is divided into external and external factors. The mechanism by which normal cells are transformed into cancer cells has not been accurately determined, but many cancers are known to be influenced by external factors such as environmental factors.
  • the cancer may be oral cancer, liver cancer, stomach cancer, colon cancer, breast cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, cervical cancer, skin cancer, cervical cancer, ovarian cancer, colon cancer, small intestine cancer, rectal cancer, fallopian tube carcinoma, anal Proximal cancer, endometrial carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, lymph gland cancer, bladder cancer, gallbladder cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, Prostate cancer, chronic leukemia, acute leukemia, lymphocyte lymphoma, kidney cancer, ureter cancer, renal cell carcinoma, renal pelvic carcinoma, central
  • “poorly differentiated cancer (poorly differentiated cancer) or a poorly differentiated tumor (poorly differentiated tumor)” means a state in which the arrangement of the structure inside the cancer tissue is indistinctly clear.
  • the cancer classification system is based on the nature of the cancer, and generally 1, 2, 3 or 3 depending on the teratogenicity (abnormal) of the cancer. It is divided into four stages.
  • Stage 1 is a cancer in which the arrangement of cancer cells is almost similar to that of normal tissues.
  • Stage 1 cancers are slow to grow and invade into surrounding tissues.
  • stage 3 or 4 cancers look completely different from normal cells or normal tissues, grow faster than stage 1 or 2 cancers and rapidly invade surrounding tissues. This is summarized as follows.
  • GX stage in which precancerous-cancer stage cannot be determined
  • low-differentiated cancers contain a large amount of cancer stem cells, high tumor boundaries, fast metastasis, poor therapeutic effect, and poor prognosis after treatment, compared to highly differentiated or moderately differentiated cancers.
  • cancer stem cell refers to a cancer cell of a comprehensive meaning having self-renewal or differentiation ability that is unique to stem cells, for example, sphere form. Cancer cell populations and cancer tissues of poorly differentiated and poor prognosis, such as low-differentiation cancer. Normal tumor growth conditions of the cancer stem cells (the "normal tumor growth conditions” refers to a state in which there is sufficient cell nutrients (glucose) necessary for cell growth and growth conditions of the tumor microenvironment, so that there is no cellular stress.) Unlike cancer cells, they may have a slower rate of proliferation or maintain a dormant state and may have resistance to anticancer drugs. For example, expression of transcriptional regulators such as PGC-1a is controlled unlike normal tumor cells.
  • the function of key metabolic regulators may be different compared to normal cancer cells. Through these different metabolic control mechanisms and mechanisms of mechanisms linked to these signaling pathways, we acquire resistance to apoptosis in nutrient deprivation and refer to cells that are invasive and / or metastatic. . However, any cell that can differentiate into a general cancer cell is not limited thereto.
  • inhibittion of growth of cancer stem cells means inhibiting cancer stem cell maintenance, inhibiting cancer stem cell malignance and inhibiting cancer stem cell invasive activity.
  • polyphenol is a kind of chemicals found in plants and is characterized by one or more phenol groups per molecule. Polyphenols are generally classified into tannins, phenylpropanoids (flavonoids, liglines, etc.). Phenol is one hydrogen atom of benzene substituted with a hydroxy group, and polyphenol is substituted with two or more hydroxy groups. There are thousands of polyphenols, including catechins in green tea, resveratrol in wine, apple and quercetin in onions. Flavonoids in fruits and isoflavones in beans are also polyphenols.
  • Polyphenols have an antioxidant effect that converts free radicals (harmful oxygen) in our body into harmless substances, preventing aging. In addition, it has been reported to lower the risk of various diseases because of its ability to protect DNA damage, cellular proteins and enzymes that are damaged by exposure to free radicals.
  • certain polyphenols can be toxic to cells by the action of phenolic substituents. Typical types of polyphenolic toxins include, but are not limited to, safrole, Gossypol, and coumarins.
  • Gossypol is a poly, which is contained in the detachable pigment glands of seeds, leaves, stems, and roots of Gossypium plants and Malvaceae plants.
  • a kind of phenolic compound also called polyphenolic gossypol or cotton thread pigment. Provide plants with resistance to pests.
  • Gosipol is added to poultry feed, feed availability, decreased egg productivity and egg yolk discoloration have been reported.
  • the ruminant axis on the other hand, inactivates Gosipol by fermentation. Free gopopol is physiologically toxic while bound gopopol is inactive. Non-protein components in cotton yarn also combine with Gosipol to form insoluble and / or non-digestible complexes.
  • Gosipol in the present invention is preferably a compound represented by the following formula (1) or derivatives thereof, but is not limited thereto.
  • biguanide-based compound is preferably a biguanide-based diabetes treatment agent, more preferably metformin, phenformin, buformine But it is not limited to any biguanide-based compounds that interfere with the production of energy in the cell to induce a nutritional deficiency-like state.
  • anticancer agent is a generic term for chemotherapeutic agents used for the treatment of malignant tumors. Most anticancer drugs intervene in various metabolic pathways of cancer cells and mainly inhibit the synthesis of nucleic acids or exhibit anticancer activity. Anticancer drugs currently used for cancer treatment are classified into six categories according to biochemical mechanisms of action.
  • Alkylating agents A highly reactive substance with the ability to introduce an alkyl group R-CH2 to a compound, and when reacted to a cell, most of it reacts with the N7 of guanine in the DNA to modify its DNA structure, and It causes cleavage and shows anticancer effect and cytotoxic effect.
  • Examples of drugs belonging to the above include: 1) nitrogen mustard system: nitrogen mustard, chlorambucil, melphalan, cyclophosphamide, etc.
  • ethyleneimine type thiotepa 3 alkylsulfonate system: sulphate 4 tri Azine, hydrazine: DTIC (daccarbine), procarbazine 5 nitrosourea: BCNU, CCNU, methyl-CCNU and the like.
  • metabolic antagonists drugs belonging to this group have the effect of inhibiting metabolic processes necessary for the proliferation of cancer cells 1 folic acid derivatives: mesotrexate (MTX) 2 purine derivatives: 6-mercaptopurine (6-MP), 6-thioguanine 3 pyrimidine derivatives: 5-fluorouracil, cytarabine and the like.
  • MTX mesotrexate
  • 6-MP 6-mercaptopurine
  • 6-thioguanine 3 pyrimidine derivatives 5-fluorouracil, cytarabine and the like.
  • Antibiotics Among antibiotics produced by bacteria, anti-cancer activity includes adriamycin, daunorubicin, bleomycin, mitomycin-C, and actinomycin-D.
  • vinca alkaloids These drugs are specific to the mitotic phase and stop cell division in the metaphase during mitotic phase. Vincristine, vinblastine, VP-16-213 and VM-26.
  • Hormone Some types of cancer can be treated with hormones. Male hormones are used to treat breast cancer, female hormones to prostate cancer, progesterone to endometrial cancer, and corticosteroids. Is used for the treatment of acute lymphocytic leukemia and lymphoma, and tamoxifen, an anti-female hormone, is used for breast cancer.
  • Irinotecan is a kind of anticancer agent used in recurrent, metastatic gastric cancer, rectal cancer or colon cancer, and preferably, irinotecan hydrochloride, but is not limited thereto.
  • diagnosis refers to confirming the presence or characteristics of a pathological condition, and for the purpose of the present invention, the diagnosis is to confirm the presence or absence of cancer, proliferation, and metastasis.
  • Cancer means“ cancer stem cells ”.
  • Cancer can be diagnosed by visual or cytological confirmation of tissue from a patient suspected of developing cancer or metastasis, and a sample of tissue suspected of developing cancer or metastasis (clinically, cells, blood, sap, pleural fluid, ascites, joint fluid, pus) (Iv), secretion, bile, pharyngeal mucus, urine, bile, stool, etc.), using a cancer-compatible antibody, directly detecting a cancer-related protein in the sample, or encoding a cancer-related protein Cancer can be diagnosed by direct detection of nucleic acids.
  • Diagnostic means using antigen-antibody binding or direct detection of cancer-related proteins include Western blot, enzyme linked immunosorbent assay (ELISA), radioimmunoassay (RIA), radioimmunodiffusion, and ouktero. Ouchterlony immune diffusion, rocket immunoelectrophoresis, tissue immunostaining, immunoprecipitation assay, complement fixation assay, fluorescence activated cell sorter (FACS), protein chip ( protein chip), but the present invention is not limited thereto, and methods for directly detecting nucleic acids encoding cancer-related proteins include reverse transcriptase (RT-PCR), competitive reverse transcriptase (RT) PCR, and real-time. Reverse Transcription Polymerase Reaction (Real-time RT-PCR), RNase Protection Assay (RPA), Northern Blotting or DNA Chips. It doesn't happen.
  • RT-PCR reverse transcriptase
  • RT competitive reverse transcriptase
  • RPA RNase Protection Assay
  • treatment refers to a series of activities performed to alleviate or / or ameliorate a desired disease.
  • Treatment for the purposes of the present invention inhibits the numerical or quantitative proliferation of cancer cells, including cancer stem cells, kills cancer cells, inhibits the growth of cancer tissues, reduces the size of cancer tissues, cancer tissues Activity that inhibits the development of neovascularization within.
  • cancer means that cancer cells leave the primary organs and go to other organs
  • cancer means “cancer stem cells”.
  • the spread of cancer to other parts of the body is largely divided into primary cancers in which the cancerous tissue grows and directly invades the surrounding organs and distantly metastasizes along the blood vessels or lymphatic vessels to other organs in the distance. Metastasis can be regulated through inhibition of expression of a gene associated with cancer development or inhibition of protein activity of the gene.
  • a pharmaceutical composition means a composition to be administered for a specific purpose.
  • a pharmaceutical composition of the present invention comprises a polyphenol compound and is used to treat or inhibit the metastasis of cancer, including cancer stem cells, and the compounds and pharmaceutically acceptable carriers, excipients or Diluents.
  • the pharmaceutical composition according to the present invention may be provided further comprising a biguanide compound and an anticancer agent in the polyphenol compound, the biguanide compound is phenformin, and the anticancer agent is irinotecan (Irinotecan). Is preferably, but is not limited thereto.
  • the pharmaceutical composition according to the present invention contains 0.1 to 50% by weight of the active ingredient of the present invention based on the total weight of the composition.
  • Carriers, excipients and diluents that may be included in the compositions of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • “administration” means introducing the composition of the invention to the patient in any suitable way, the route of administration of the composition of the invention via any general route as long as it can reach the target tissue. May be administered.
  • the effective amount is defined as the type of disease, the severity of the disease, the type and amount of the active ingredient and other ingredients contained in the composition, the type and formulation of the patient and the age, body weight, general health condition, sex and diet, time of administration, route of administration And various factors, including the rate of secretion of the composition, the duration of treatment, and the drugs used concurrently.
  • the therapeutic pharmaceutical composition can be administered once in the body in an amount of 50ml ⁇ 500ml, 0.1ng / kg-10mg / kg for a compound, 0.1ng / kg-10mg for a monoclonal antibody. It may be administered at a dose of / kg.
  • Dosing interval may be 1 to 12 times a day, if 12 times a day may be administered once every two hours.
  • the pharmaceutical composition of the present invention may be administered alone or in combination with other therapies known in the art for the treatment of cancer stem cells of interest, such as chemotherapeutic agents, radiation and surgery.
  • the pharmaceutical compositions of the present invention may also be administered in admixture with other therapies designed to enhance immune responses, for example adjuvant or cytokines (or nucleic acids encoding cytokines), as is well known in the art.
  • Other standard delivery methods may be used, such as biolistic delivery or ex vivo treatment.
  • APCs antigen presenting cells
  • dendritic cells dendritic cells
  • peripheral blood mononuclear cells peripheral blood mononuclear cells
  • bone marrow cells can be obtained from a patient or appropriate donor and then activated in vitro with the pharmaceutical composition and then administered to the patient. have.
  • a pharmaceutical composition for preventing or treating cancer comprising a polyphenol compound as an active ingredient, wherein the polyphenol compound is safrole, Gossypol, and coumarins. It provides a pharmaceutical composition which is at least one selected from the group consisting of, wherein the polyphenol compound provides a pharmaceutical composition contained in an amount of 0.5 to 500 mM, the pharmaceutical composition further comprises a biguanide compound
  • the biguanide-based compound provides a pharmaceutical composition of any one or more selected from the group consisting of metformin, buformin, and phenformin, wherein the pharmaceutical composition is It provides a pharmaceutical composition further comprising an anticancer agent, wherein the anticancer agent provides a pharmaceutical composition which is Irinotecan (Irinotecan), the cancer
  • Providing a pharmaceutical composition comprising cancer stem cells wherein the cancer provides a pharmaceutical composition that is gastric cancer, wherein the treatment inhibits the increase in the number of cancer cells, including cancer stem cells, inhibit
  • a pharmaceutical composition for inhibiting cancer metastasis comprising a polyphenol compound as an active ingredient, wherein the polyphenol compound is safrole, Gossypol, and coumarins.
  • a pharmaceutical composition which is at least one selected from the group consisting of, wherein the polyphenol compound provides a pharmaceutical composition comprising an amount of 0.5 to 500 mM, the pharmaceutical composition further comprises a biguanide-based compound
  • the biguanide-based compound provides a pharmaceutical composition of any one or more selected from the group consisting of metformin, buformin, and phenformin
  • the pharmaceutical composition is an anticancer agent
  • the anticancer agent provides a pharmaceutical composition is Irinotecan (Irinotecan), the cancer It provides that the pharmaceutical composition comprising the stem cells, the cancer is gastric cancer provides a pharmaceutical composition.
  • Cancer stem cells are cancer cells with unlimited regenerative capacity similar to those of general stem cells, and slowly proliferate differently from general cancer cells, and have a mechanism of self-renewal or differentiation, which is unique to stem cells, and different mechanisms from known cancer cells. It is known to have mechanism. If cancer stem cells remain in the body even after cancer treatment, cancer recurrence and / or metastasis occurs actively, so developing cancer stem cell therapeutics is an urgent task.
  • the present invention relates to a pharmaceutical composition for treating cancer comprising a polyphenol compound as an active ingredient, wherein the pharmaceutical composition according to the present study is for treating cancer tissue including cancer stem cells or cancer stem cells in large amounts such as low-differentiated cancer. And very effective in improving prognosis.
  • polyphenol compounds, biguanide-based compounds, and anticancer agents are used in combination with cancer cells, and thus, the effects of inhibiting cancer cell growth are significantly increased compared to those administered alone, and are expected to be greatly utilized in the field of cancer treatment.
  • Figure 2 is in accordance with an embodiment of the present invention, the result of confirming the ATP synthesis inhibitory effect of Gosipol on gastric cancer cell line.
  • Figure 3 is a diagram confirming the cell death promoting effect of Gosipol on gastric cancer cell line according to an embodiment of the present invention.
  • Figure 4 is a graph confirming the cell death promoting effect of Gosipol on gastric cancer cell line according to an embodiment of the present invention.
  • Figure 9 is a result confirming the cell growth inhibitory effect when combined administration of Gosipol and conventional drugs to the gastric cancer cell line according to an embodiment of the present invention.
  • Figure 11 shows the results of confirming the cell death effect in combination administration of Gosipol and conventional drugs to the gastric cancer cell line according to an embodiment of the present invention.
  • FIG. 12 is a graph showing the results of confirming the cell killing effect when co-administration of gosipol and the existing drug to the gastric cancer cell line according to an embodiment of the present invention.
  • Cancer cells that survived for 4 weeks of continuous metabolic stress from normal gastric cancer cell AGS were expressed as cancer stem cell markers, tumor spheroid forming ability, standard anticancer drug resistance, and tumor forming ability in immunosuppressive mice.
  • the growth inhibition effect by gosipol was confirmed for AGS cells (SAGS, selected AGS, Cell Death Dis. 2015 Jul 2; 6: e1805) selected by phenotypic analysis.
  • Cell culture and viability measurement method was performed in the same manner as in Example 2-1.
  • the stained plates were dried at room temperature and 100 ⁇ l of 10 mM Tris buffer (pH 7.5) was added to each well, and the eluted pigment was absorbed at 515 nm. Growth inhibition effect of the cancer cell line according to the goshipol concentration derived as the above result is described in FIG.
  • ATP adenosine triphosphate
  • MKN28, MKN45 and SNU668 of Example 1-1 were confirmed to inhibit the ATP synthesis of Gosipol.
  • MKN28, MKN45, and each cell of the SNU668 (cell number; 1 X 10 3 - 1 X 10 4 / plate) were incubated for 24 hours in 60mm culture dishes and treated for examination pole in each 0, 10, or the concentration of 20 ⁇ M Then, incubated for an additional 48 hours. Cells were then harvested and counted and diluted in 100 ⁇ l of RPMI culture with 10 volume% FBS, which was transferred to each well of a 96-well plate.
  • the Gosipol 0 ⁇ M treated control cells were divided into 4 groups, each non-stained, Annexin V stained, propidium iodide (PI) stained and Annexin V + PI stained, and treated with Gosipol 5, 10, or 20 ⁇ M, respectively.
  • One cell was stained with Annexin V + PI. Staining of cells was performed for 10 minutes in the dark. The stained cells were subjected to flow cytometry (FACS) to derive cell death rate to total cells. The results are shown in FIGS. 3 to 4 (BD Biosciendes, # 556547).
  • MKN28 differentiated cells
  • gosypol concentrations 0 5 ⁇ M, respectively.
  • Cases were 11.77 &, 45.75%, 65.8% and 82.22%.
  • the results showed that the cell death rate of MKN45 (low-differentiating cells) was higher than that of MKN28 (low-differentiating cells) at all concentrations of Gosipol-treated cells. .
  • Gosipol is expected to have a significant effect on the growth inhibition of cancer stem cells.
  • Example 1-1 Six different gastric cancer cell lines (MKN28, MKN45, AGS, SNU668, Kato3 and HS746T) of Example 1-1 were incubated for 24 hours in a 100 mm culture dish of 1 ⁇ 10 3 to 1 ⁇ 10 4 / well, respectively, Gosipol was treated at a concentration of 0 or 10 ⁇ M and then incubated for an additional 24 hours. Gosipol treated cells were obtained, fixed with 70% ethanol, washed with cold 1X PBS, and stained with PI + RNase solution (DPBS, pH7.4) in the dark for 30 minutes. The cells were subjected to flow cytometry (FACS) to analyze the ratio of cell cycles by DNA content. The results are shown in FIG.
  • FACS flow cytometry
  • Each well containing immobilized cells was stained with 100 ⁇ l of 0.4 wt% Sulforhodamine B dissolved in 1 vol% acetic acid solution for 10 min and washed 4 times with 1 vol% acetic acid solution.
  • the stained plates were dried at room temperature and 100 ⁇ l of 10 mM Tris buffer (pH 7.5) was added to each well, and the eluted pigment was absorbed at 515 nm. 6 and 7 show the results of calculating the concentration of Gosipol from which the viability of each cell becomes IC50.
  • Example 2-2 For stem cells selected and isolated from cancer cells Gossip Confirmation of growth inhibitory effect
  • Cancer cells that survived for 4 weeks of continuous metabolic stress from normal gastric cancer cell AGS were expressed as cancer stem cell markers, tumor spheroid forming ability, standard anticancer drug resistance, and tumor forming ability in immunosuppressive mice.
  • the growth inhibition effect by gosipol was confirmed for AGS cells (SAGS, selected AGS, Cell Death Dis. 2015 Jul 2; 6: e1805) selected by phenotypic analysis.
  • Cell culture and viability measurement method was performed in the same manner as in Example 2-1.
  • Example 3-1 Analysis of Cell Growth of Gastric Cancer Cells Treated with Gosipol and Existing Drugs
  • AGS, SNU484, SNU668, MKN28, Hs746T, MKN45, and SNU719 gastric cancer stem cells were inoculated in 96-well plates at 5 ⁇ 10 3 to 4 ⁇ 10 4 / well, respectively, and incubated for 24 hours. Each well was then administered with Gosipol, Phenformin, and Irinotecan drugs as shown in Table 3 and incubated for an additional 24 hours. Thereafter, the cells were fixed with 50 vol% TCA (trichloroacetic acid, final concentration of 10% TCA) for 1 hour at 4 ° C., washed with distilled water, and then dried at room temperature.
  • TCA trichloroacetic acid, final concentration of 10% TCA
  • Each well containing immobilized cells was stained with 100 ⁇ l of 0.4 wt% Sulforhodamine B dissolved in 1 vol% acetic acid solution for 10 min and washed 4 times with 1 vol% acetic acid solution.
  • the stained plates were dried at room temperature and 100 ⁇ l of 10 mM Tris buffer (pH 7.5) was added to each well, and the eluted pigment was absorbed at 515 nm.
  • the growth inhibitory effect of the gastric cancer cell line derived as a result is described in FIG. 9.
  • Example 3-2 Gossipol And mitochondrial activity of gastric cancer cells treated with conventional drugs
  • Mitochondrial cell membrane activity analysis was performed on the control and Experimental Examples 1 to 7 cells of Example 3-1. Mitochondrial cell membrane activity is used as an indicator of intracellular energy production. First, 100 nM TMRE (tetramethylrodamine ester, ab113852, Abcam) was added to the culture medium 20 minutes before the end of drug treatment of each cell sample, the cells were washed three times with cold PBS, and then 585 nm (FL) with a flow cytometer. -2) the fluorescence intensity of the cells was measured using the channel. The results are shown in FIG.
  • TMRE tetramethylrodamine ester, ab113852, Abcam
  • the combination of gosypol, phenformin, and irinotecan showed a significant decrease in mitochondrial activity than that of gosypol and phenformin alone. This can be judged to lower the energy production of cancer cells.
  • Example 3-3 Analysis of Cell Death of Gastric Cancer Cells Treated with Gosipol and Conventional Drugs
  • Example 3-1 For the control and Experimental Examples 1 to 7 cells of Example 3-1, samples were taken at 12 hours, 24 hours, 48 hours, and 72 hours after each drug administration, and cell death analysis was performed. First, the cells were washed with cold PBS, centrifuged at 1400 rpm for 3 minutes and then resuspended at a concentration of 1 x 10 6 cells / ml. 100 ⁇ l of the cell suspension was transferred to a 5 ml culture tube, 5 ⁇ l of Annexin V-FITC and PI stain were added, respectively, and reacted for 15 minutes at dark room temperature. 400 ⁇ l of 1 ⁇ binding buffer was added to the FACS flow cytometer (BD Falcon, Bedford, Mass., USA).
  • FIGS. 11 and 12 Graphs converted into FACS results and numerical values are shown in FIGS. 11 and 12. The results of the study showed that when Gossipol, Penformin, and Irinotecan were co-administered at all times, Gossipol, Penformin, or Itinotecan were administered alone, and Gossipol and Penformin were co-administered. More significantly, cancer cell death was shown to increase.
  • the present invention relates to a pharmaceutical composition for treating cancer comprising a polyphenol compound as an active ingredient, wherein the pharmaceutical composition according to the present study is for treating cancer tissue including cancer stem cells or cancer stem cells in large amounts such as low-differentiated cancer. And very effective in improving prognosis.
  • polyphenol compounds, biguanide-based compounds, and anticancer agents are used in combination with cancer cells, and thus, the effects of inhibiting cancer cell growth are significantly increased compared to those administered alone, and are expected to be greatly utilized in the field of cancer treatment.

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Abstract

La présente invention concerne une composition pharmaceutique pour le traitement d'un cancer, contenant un composé polyphénol utilisé comme principe actif. La composition pharmaceutique selon la présente étude est très efficace pour le traitement et l'amélioration du diagnostic de cellules souches cancéreuses ou de tissus cancéreux présentant un grand nombre de cellules souches cancéreuses tels que dans un cancer faiblement différencié. De plus, le composé polyphénol et un composé biguanide, et un agent anticancéreux se sont avérés augmenter de façon remarquable les effets inhibiteurs sur la croissance de cellules cancéreuses lorsqu'ils sont administrés à des cellules cancéreuses en association plutôt qu'individuellement, de sorte que la composition est susceptible de trouver des applications importantes dans le domaine de la thérapie anticancéreuse.
PCT/KR2017/001783 2016-02-18 2017-02-17 Composition pharmaceutique pour le traitement d'un cancer, contenant un composé polyphénol utilisé comme principe actif WO2017142348A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
CN201780013437.0A CN108697667A (zh) 2016-02-18 2017-02-17 用于治疗癌症、含有多酚化合物作为活性成分的药物组合物
US15/999,726 US10864178B2 (en) 2016-02-18 2017-02-17 Pharmaceutical composition for treatment of cancer containing polyphenol compound as active ingredient
EP17753509.3A EP3417853B1 (fr) 2016-02-18 2017-02-17 Composition pharmaceutique pour le traitement d'un cancer de l'estomac contenant gossypol, phenformin et irinotecan
JP2018536492A JP6829723B2 (ja) 2016-02-18 2017-02-17 ポリフェノール化合物を有効成分として含む癌治療用薬学組成物
IL261196A IL261196B (en) 2016-02-18 2018-08-16 A pharmaceutical preparation for the treatment of cancer, containing a polyphenol compound as an active ingredient
HK18116737.4A HK1257615A1 (zh) 2016-02-18 2018-12-28 用於治療癌症、含有多酚化合物作為活性成分的藥物組合物

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