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WO2019147089A1 - Composition pharmaceutique pour la prévention ou le traitement du cancer comprenant, en tant que substance active, un inhibiteur calcique ou un sel pharmaceutiquement acceptable de celui-ci - Google Patents

Composition pharmaceutique pour la prévention ou le traitement du cancer comprenant, en tant que substance active, un inhibiteur calcique ou un sel pharmaceutiquement acceptable de celui-ci Download PDF

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Publication number
WO2019147089A1
WO2019147089A1 PCT/KR2019/001143 KR2019001143W WO2019147089A1 WO 2019147089 A1 WO2019147089 A1 WO 2019147089A1 KR 2019001143 W KR2019001143 W KR 2019001143W WO 2019147089 A1 WO2019147089 A1 WO 2019147089A1
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Prior art keywords
cancer
calcium channel
pharmaceutical composition
cells
channel inhibitor
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PCT/KR2019/001143
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English (en)
Korean (ko)
Inventor
민상현
김준우
이희진
유지훈
최동규
송영우
최재헌
김재호
Original Assignee
재단법인 대구경북첨단의료산업진흥재단
부산대학교 산학협력단
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Publication of WO2019147089A1 publication Critical patent/WO2019147089A1/fr

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/308—Foods, ingredients or supplements having a functional effect on health having an effect on cancer prevention
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to a pharmaceutical composition for preventing or treating cancer, which comprises a calcium channel inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Stem cells are immature cells that can undergo self-renewal and can differentiate into the cells of each organ and achieve organogenesis.
  • Adult stem cells are distinguishable from embryonic stem cells in that they are identical to embryonic stem cells in that they can regenerate and differentiate, but differentiation is mainly made up of specific endothelial cells.
  • a representative example of adult stem cells is hematopoietic stem cells.
  • Cancer stem cells like stem cells, can regenerate and differentiate through asymmetric division, but unlike normal stem cells, they are cells that produce tumors with impaired ability to regulate division.
  • signals such as Notch, Sonic hedgehog (SHH), Wnt, ⁇ -catenin, phosphatase and tensin homolog [HONG7] (PTEN), transforming growth factor
  • SHH Sonic hedgehog
  • Wnt Wnt
  • ⁇ -catenin phosphatase and tensin homolog [HONG7]
  • PTEN tensin homolog
  • the pathway was found to be deformed in malignant tumors.
  • the expression of PTEN, Hedgehog signaling pathway, nestin, epidermal growth factor (EGF) -receptor, and proliferative potential vasculature, immature expression pattern, and high motility, progeny diversity, , telomerase activity, and Wnt signaling pathway activity.
  • Patent Document 1 Korean Patent Laid-open Publication No. 1020160094861 discloses a pharmaceutical composition for inhibiting the growth of cancer stem cells comprising an aldehyde inhibitor and an acetylated compound,
  • Non-Patent Document 1 J Korean Assoc Oral Maxillofac Surg 2011; 37: 97-108 discloses the theory of cancer stem cell in oral squamous cell carcinoma and the latest knowledge.
  • Another object of the present invention is to provide a health functional food composition for preventing or ameliorating cancer.
  • a pharmaceutical composition for preventing or treating cancer comprising as an active ingredient a calcium channel inhibitor or a pharmaceutically acceptable salt thereof.
  • a combined preparation for preventing or treating cancer comprising a calcium channel inhibitor or a pharmaceutically acceptable salt thereof and an anticancer agent.
  • a health functional food composition for preventing or ameliorating a cancer containing, as an active ingredient, a calcium channel inhibitor or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition for preventing or treating cancer comprising the calcium channel blocker or a pharmaceutically acceptable salt thereof as an active ingredient, A method of preventing or treating cancer is provided.
  • a pharmaceutical composition for preventing or treating cancer comprising the calcium channel inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient in the prevention or treatment of cancer.
  • the use of functional food compositions is provided.
  • the pharmaceutical composition comprising the calcium channel inhibitor of the present invention is excellent in the effect of inhibiting growth and proliferation of cancer stem cells even when used alone and exhibits a more excellent pharmacological effect when it is administered in combination with a conventional anticancer drug , Cancer recurrence, metastasis, and progression of cancer can be inhibited. Therefore, the composition can be usefully used as a pharmaceutical composition or a combined preparation for the prevention or treatment of cancer.
  • Figure 1 shows a dose-response curve of the viability of A2780-SP cells (ovarian cancer stem cells) when the example pharmaceutical composition is treated.
  • Figure 1 a Manidipine
  • Figure 1 b Rashedipine
  • Figure 1 c Benidipine
  • Figure 1 d shows a dose-response curve of the viability of A2780-SP cells (ovarian cancer stem cells) when the example pharmaceutical composition is treated.
  • Figure 1 a Manidipine
  • Figure 1 b Rashedipine
  • Figure 1 c Benidipine
  • Figure 1 d shows a dose-response curve of the viability of A2780-SP cells (ovarian cancer stem cells) when the example pharmaceutical composition is treated.
  • Figure 1 a Manidipine
  • Figure 1 b Rashedipine
  • Figure 1 c Benidipine
  • Figure 1 d Benidipine
  • Figure 2 shows the dose-response curve of the viability of A2780 cells (ovarian cancer cells) when the example pharmaceutical composition was treated.
  • Figure 2a Manidipine
  • Figure 2b Rashedipine
  • Figure 2c Lomerizine HCl
  • Figure 2d Benidipine HCl
  • FIG. 3 is an image showing the result of analyzing the sphere formation of A2780-SP cells (ovarian cancer stem cells) when the pharmaceutical composition of the Example was treated.
  • Figure 3a Manidipine
  • Figure 3b Rashedipine
  • Figure 3c Lomerizine HCl
  • Figure 3d Benidipine HCl
  • FIG. 4 is a graph showing the results of measurement of the proliferation of A2780-SP cells by analyzing the sphere formation of A2780-SP cells (ovarian cancer stem cells) when the pharmaceutical composition of Example was treated.
  • Figure 4a Manidipine
  • Figure 4b Rashedipine
  • Figure 4c Romerizine HCl
  • Figure 4d Benidipine HCl
  • FIG. 5 is an image showing changes in the expression of markers related to cancer stem cell function in A2780-SP cells (ovarian cancer stem cells) when the pharmaceutical composition of Example is treated.
  • Figure 6 is a graph quantifying the expression changes of markers related to cancer stem cell function in A2780-SP cells (ovarian cancer stem cells) when the example pharmaceutical composition is treated.
  • Figure 6a OCT 3/4
  • Figure 6b NANOG
  • Figure 6c SOX2
  • Figure 6d ALDHl
  • Figure 6e CD133
  • FIG. 7 is an image showing changes in the activity of proteins involved in cancer stem cell survival and proliferation in A2780-SP cells (ovarian cancer stem cells) when the pharmaceutical composition of the Example was treated.
  • FIG. 8 is a graph quantifying the change in the activity of a protein involved in cancer stem cell survival and proliferation in A2780-SP cells (ovarian cancer stem cells) when the example pharmaceutical composition is treated.
  • Figure 8a pAKT
  • Figure 8b pERK
  • Figure 8c p-p38
  • FIG. 9 is a graph showing cell cycle changes of A2780-SP cells when the example pharmaceutical composition is treated.
  • Figure 9a DMSO
  • Figure 9b Manidipine
  • Figure 9c Rashedipine
  • Figure 9d Romerizin HCl
  • Figure 9e Benidipine HCl
  • FIG. 10 is a graph showing the cell death of A2780-SP cells when the pharmaceutical composition of Example is treated.
  • Fig. 11 shows quantitative RT-PCR quantification of the expression levels of calcium channel subunits (Cacna1d, Cacna1f, Cacna1h) mRNA in A2780-SP cells and A2780 cells.
  • 11a Cacna1d
  • Fig. 11b Cacna1f
  • Fig. 11c Cacna1h
  • 12 shows the results of knockdown of the calcium channel-related genes (si-Cacna1d, si-Cacna1f, si-Cacna1h) in A2780-SP cells and the mRNA expression level of each calcium channel subunit (Cacna1d, Cacna1f, Cacna1h) Was quantitated by quantitative RT-PCR to confirm knockdown.
  • 12a Cacna1d
  • Fig. 12b Cacna1f
  • Fig. 12c Cacna1h
  • FIG. 13 shows the results of knockdown of calcium channel-related genes (si-Cacna1d, si-Cacna1f and si-Cacna1h) in A2780-SP cells and then to identify markers (OCT3 / 4, NANOG, SOX2, ALDH1 , CD133) was quantified by quantitative RT-PCR.
  • Figure 13a OCT 3/4
  • Figure 13b NANOG
  • Figure 13c SOX2
  • Figure 13d ALDHl
  • Figure 13e CD133
  • FIG. 14 is a graph showing the results of knockdown of calcium channel-related genes (si-Cacna1d, si-Cacna1f and si-Cacna1h) in A2780-SP cells, and stem cell-associated markers and the expression of proteins involved in the survival and proliferation of cancer stem cells.
  • FIG. 15 is a graph showing the results of knockdown of calcium channel-related genes (si-Cacna1d, si-Cacna1f, si-Cacna1h) in A2780-SP cells, a stem cell-associated marker, and a stem cell-associated marker and the expression of a protein associated with survival and proliferation of cancer stem cells.
  • Figure 15a OCT 3/4
  • Figure 15b pERK
  • Figure 15c p-p38
  • Figure 16 is a graph showing that the amplitude of calcium current is reduced when the pharmaceutical composition of Example is treated with A2780-SP cells.
  • FIG. 17 is a graph showing the results of measuring the cell survival rate of A2780-SP cells when the pharmaceutical composition of Example and cisplatin were used in combination.
  • FIG. Figure 17a Manidipine
  • Figure 17b Rashedipine
  • Figure 17c Romerizin HCl
  • Figure 17d Benidipine HCl
  • FIG. 18 is a graph showing the results of analysis of cell proliferation of A2780-SP cells when the pharmaceutical composition of Example and cisplatin were used in combination.
  • Figure 18a Manidipine
  • Figure 18b Rashedipine
  • Figure 18c Romerizin HCl
  • Figure 18d Benidipine HCl
  • FIG. 19 is a graph showing the results of tumorigenesis (A2780-AD) in the case of the ovarian cancer cell tumor animal model (A2780-AD) and the ovarian cancer stem cell tumor animal model (A2780-SP), alone or in combination with paclitaxel Inhibitory effect and evaluating the results.
  • 19A A2780-AD
  • FIG. 19B A2780-SP
  • An aspect of the present invention provides a pharmaceutical composition for preventing or treating cancer comprising as an active ingredient a calcium channel inhibitor or a pharmaceutically acceptable salt thereof.
  • the calcium channel inhibitor may be any one selected from the following formulas (A) to (D).
  • the cancer may be selected from the group consisting of benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, brain lymphoma, oligodendroglioma, intracranial lesion, ependymoma, brain tumor, laryngeal cancer, pancreatic cancer, nasopharyngeal carcinoma, nasopharyngeal carcinoma, Cancer of the breast, cancer of the gallbladder, cancer of the gallbladder, cancer of the bile duct, pancreatic cancer, small bowel cancer, colon cancer, anal cancer, bladder cancer, breast cancer, Kidney cancer, penile cancer, prostate cancer, cervical cancer, endometrial cancer, ovarian cancer, uterine sarcoma, vaginal cancer, female gonadal cancer and skin cancer.
  • the cancer may be an ovarian cancer.
  • the pharmaceutical composition may inhibit expression of at least one selected from the group consisting of proteins consisting of OCT3 / 4, NANOG, SOX2, ALDH1, CD133, pAKT, AKT, p-ERK, ERK, p-p38 and p38.
  • the pharmaceutical composition can inhibit the proliferation of cancer stem cells.
  • the anticancer effect of the pharmaceutical composition was measured.
  • the pharmaceutical composition reduced the viability of cancer cells and cancer stem cells, suppressed proliferation, inhibited the formation and proliferation of cancer stem cells
  • the anticancer effect was excellent because the cancer stem cell-related marker and the effect of suppressing the expression of the protein related to the proliferation were excellent and the cell death of the cancer stem cell was increased (Experimental Examples 2 to 5 and FIGS. 10).
  • the pharmaceutical composition according to one aspect of the present invention can be usefully used as a pharmaceutical composition for preventing or treating cancer.
  • the calcium channel inhibitor may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful.
  • Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid and the like, aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, And organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like are obtained from non-toxic organic acids such as dicarboxylic acids, Examples of such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite,
  • the acid addition salt can be prepared by a conventional method.
  • the calcium channel inhibitor is dissolved in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc., and a precipitate formed by adding an organic acid or an inorganic acid is filtered, dried Or by distilling the solvent and excess acid under reduced pressure, followed by drying and crystallization in an organic solvent.
  • bases can be used to make pharmaceutically acceptable metal salts.
  • the alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt.
  • the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable salt (such as silver nitrate).
  • the calcium channel inhibitor may be used in the form of a pharmaceutically acceptable salt thereof, as well as a solvate, an optical isomer, a hydrate, etc., which may be prepared therefrom.
  • the calcium channel blocker or a pharmaceutically acceptable salt thereof may be administered in various forms of oral and parenteral administration at the time of clinical administration.
  • a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used.
  • Solid formulations for oral administration include tablets, pills, powders, granules, capsules, and the like, which may contain one or more excipients such as starch, calcium carbonate, sucrose or lactose lactose, gelatin and the like.
  • lubricants such as magnesium stearate, talc, and the like are also used.
  • Liquid preparations for oral administration include suspensions, solutions, emulsions, syrups and the like.
  • excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included in addition to water and liquid paraffin, which are simple diluents commonly used. have.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, and emulsions.
  • the non-aqueous solvent and the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate.
  • the pharmaceutical composition comprising the calcium channel blocker or a pharmaceutically acceptable salt thereof as an active ingredient may be administered parenterally, and the parenteral administration may be a subcutaneous injection, an intravenous injection, an intramuscular injection, And.
  • the calcium channel blocker or pharmaceutically acceptable salt thereof is mixed with water or a stabilizer or a buffer to prepare a solution or suspension, which is then prepared into an ampoule or vial unit dosage form .
  • the compositions may contain sterilized and / or preservatives, stabilizers, wettable or emulsifying accelerators, adjuvants such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, Or may be formulated according to the coating method.
  • formulations for oral administration include tablets, pills, light / soft capsules, liquids, suspensions, emulsions, syrups, granules, elixirs and troches, , Dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants (such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols).
  • the tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine and may optionally contain binders such as starch, agar, alginic acid or sodium salts thereof Release or boiling mixture and / or absorbent, colorant, flavor, and sweetening agent.
  • binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine and may optionally contain binders such as starch, agar, alginic acid or sodium salts thereof Release or boiling mixture and / or absorbent, colorant, flavor, and sweetening agent.
  • Another aspect of the present invention provides a combined preparation for prevention or treatment of cancer comprising a calcium channel inhibitor or a pharmaceutically acceptable salt thereof and an anticancer agent.
  • the calcium channel inhibitor may be any one selected from the following formulas (A) to (D).
  • the cancer may be selected from the group consisting of benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, brain lymphoma, oligodendroglioma, intracranial lesion, ependymoma, brain tumor, laryngeal cancer, pancreatic cancer, nasopharyngeal carcinoma, nasopharyngeal carcinoma, Cancer of the breast, cancer of the gallbladder, cancer of the gallbladder, cancer of the bile duct, pancreatic cancer, small bowel cancer, colon cancer, anal cancer, bladder cancer, breast cancer, Kidney cancer, penile cancer, prostate cancer, cervical cancer, endometrial cancer, ovarian cancer, uterine sarcoma, vaginal cancer, female gonadal cancer and skin cancer.
  • the cancer may be an ovarian cancer.
  • the combined preparation may inhibit expression of at least one selected from the group consisting of OCT3 / 4, NANOG, SOX2, ALDH1, CD133, pAKT, AKT, p-ERK, ERK, p-p38 and p38.
  • the combined preparation can inhibit the proliferation of cancer stem cells.
  • anticancer agent is a generic term for known drugs used in conventional cancer therapy that act on various metabolic pathways of cancer cells and exhibit cytotoxicity or cytostatic effects on cancer cells. Metabolic antagonists, botanical alkaloids, topoisomerase inhibitors, alkylating agents, anticancer antibiotics, hormones and other medicaments.
  • the anticancer agent is selected from the group consisting of doxorubicin, paclitaxel, vincristine, daunorubicin, vinblastine, actinomycin-D, docetaxel, etoposide, (Including but not limited to: teniposide, bisantrene, homoharringtonine, Gleevec (STI-571), cisplatin, 5-fluorouracil, adriamycin, methotrexate, busulfan, chlorambucil chlorambucil, cyclophosphamide, melphalan, nitrogen mustard, and nitrosourea.
  • doxorubicin doxorubicin
  • paclitaxel paclitaxel
  • vincristine daunorubicin
  • vinblastine actinomycin-D
  • docetaxel etoposide
  • etoposide including but not limited to: teniposide, bisantrene, homoharringtonine, Gleevec
  • the anticancer agent may be cisplatin or paclitaxel.
  • the pharmaceutical composition containing the calcium channel blocker exhibits excellent cell proliferation inhibitory effect even when it is administered alone.
  • the cell proliferation of stem cells is further suppressed (see Experimental Example 7 and Figs. 17 and 18).
  • the calcium channel inhibitor of the present invention or a pharmaceutically acceptable salt thereof exhibits excellent anticancer effects even when used alone, and can exhibit higher synergistic effects when used in combination with existing anticancer drugs.
  • the combined preparation according to one aspect of the present invention can be usefully used for the prevention or treatment of cancer by the combined use with the conventional anticancer agent.
  • Another aspect of the present invention provides a combination therapy for prevention or treatment of cancer, which is used by administering a combination of a calcium channel inhibitor, a pharmaceutically acceptable salt thereof and an anticancer agent.
  • the combined administration can be carried out simultaneously, separately or sequentially.
  • Another aspect of the present invention provides a health functional food composition for preventing or ameliorating cancer, which comprises a calcium channel inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the calcium channel inhibitor may be any one selected from the following formulas (A) to (D).
  • the cancer may be selected from the group consisting of benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, brain lymphoma, oligodendroglioma, intracranial lesion, ependymoma, brain tumor, laryngeal cancer, pancreatic cancer, nasopharyngeal carcinoma, nasopharyngeal carcinoma, Cancer of the breast, cancer of the gallbladder, cancer of the gallbladder, cancer of the bile duct, pancreatic cancer, small bowel cancer, colon cancer, anal cancer, bladder cancer, breast cancer, Kidney cancer, penile cancer, prostate cancer, cervical cancer, endometrial cancer, ovarian cancer, uterine sarcoma, vaginal cancer, female gonadal cancer and skin cancer.
  • the cancer may be an ovarian cancer.
  • health functional food refers to a food prepared by adding the calcium channel inhibitor to food materials such as beverage, tea, spices, gum, confectionery, etc., encapsulation, powdering, suspension, etc., But it has the advantage that there are no side effects that can occur when a drug is used for a long period of time using a food as a raw material.
  • the health functional food of the present invention thus obtained can be ingested on a daily basis, so that a high skin whitening effect can be expected, which is very useful.
  • the calcium channel blocker or pharmaceutically acceptable salt thereof may be added directly to the food or may be used together with other food or food ingredients and may be suitably used according to conventional methods.
  • the amount of the active ingredient to be mixed can be suitably determined according to the intended use (for prevention or improvement). Generally, the amount of the compound in the health functional food may be 0.1 to 90 parts by weight based on the total weight of the food. However, in the case of long-term intake intended for health and hygiene purposes or for the purpose of controlling health, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount exceeding the above range.
  • the health functional beverage composition according to one aspect of the present invention has no particular limitation on other ingredients except that the calcium channel inhibitor is contained as an essential ingredient in the indicated ratio, and various flavors or natural carbohydrates As an additional component.
  • natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And polysaccharides, for example, conventional sugars such as dextrin, cyclodextrin and the like, and sugar alcohols such as xylitol, sorbitol and erythritol.
  • Natural flavors can be advantageously used as flavors other than those described above
  • the ratio of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 g of the composition of the present invention.
  • the calcium channel inhibitor of the present invention or a pharmaceutically acceptable salt thereof may be in the form of a flavoring agent such as various nutrients, vitamins, minerals (electrolytes), manufacturing flavors and natural flavors, Etc.), pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloid thickening agents, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated drinks and the like.
  • the calcium channel inhibitor of the present invention or a pharmaceutically acceptable salt thereof may contain natural fruit juice and pulp for the production of fruit juice drinks and vegetable drinks.
  • a method for preventing or treating cancer comprising the calcium channel inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient, And a method for preventing or treating cancer.
  • Another aspect of the present invention is a pharmaceutical composition for preventing or treating cancer comprising the calcium channel inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient in the prevention or treatment of cancer.
  • a food composition comprising the calcium channel inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient in the prevention or treatment of cancer.
  • compositions of Examples 1 to 3 were prepared using the following three test substances as calcium channel inhibitors.
  • A2780-SP cells (ovarian cancer stem cells) were plated in Ultra-Low Attachment round bottom 96-well corning at a viable cell density of 500 cells per well and cultured in Cancer stem cell medium.
  • Cancer stem cell culture medium consists of neurobasal medium supplemented with bFGF 20 ng / ml, EGF 10 ng / ml, Amphotericin B 2.5 ng / ml, HEPES, Glutamax and B27. The cells were centrifuged lightly and cultured.
  • apigenin-treated control group was treated with 0% and DMSO-treated control group was treated with 100%. As a result, the size and viability of spherical cells were reduced to less than 10% of DMSO treatment.
  • Normal fibroblast cells BJ6 and NIH-3T3, were plated at a viable cell density of 3000 cells per well on a 96-well cell culture plate to determine if these compounds are generally cytotoxic stem cell culture medium. After culturing for 24 hours, the selected compounds were treated with a single concentration of 10 nM and cultured for 72 hours. Cell-titer glo (Promega, WC, USA) was then treated for luciferase activity to compare viability. Luciferase activity was detected using a Tecan plate reader (Biocompare, USA). DMSO-treated control cells were divided into 100% and 0% cells, respectively.
  • Example 1 Benidipine hydrochloride 5 0 2 (Example 2) Lacidipine (Lacipil, Motens) 5 0 3 (Example 3) Manidipine (Manyper) 2 0 4 (Example 4) Lomerizine HCl 2 0 5 Cilnidipine 18 14 6 Ranolazine dihydrochloride 86 87 7 Isradipine (Dynacirc) 48 20 8 Amlodipine (Norvasc) 21 4 9 Flunarizine 2HCl 12 0 10 Cleviprex (Clevidipine) 96 64 11 Nitrendipine 95 89 12 Tetracaine hydrochloride (Pontocaine) 46 17 13 Nilvadipine (ARC029) 28 32 14 Azelnidipine 98 0 15 Nicardipine HCl 29 57 16 Nimodipine (Nimotop) 78 64 17 Nisoldipine (Waters) 78 52 18 Nife
  • a total of 20 kinds of calcium channel inhibitors were screened. However, only four kinds of compounds of the present invention show an area value of 5 or less, and at the same time, the ATP measurement value is zero.
  • A2780-SP cells were plated in Ultra-Low Attachment round-bottomed 96-well corning at a viable cell density of 500 cells per well and cultured in cancer stem cell medium.
  • Cancer stem cell culture medium consists of neurobasal medium supplemented with bFGF 20 ng / ml, EGF 10 ng / ml, Amphotericin B 2.5 ng / ml, HEPES, Glutamax and B27.
  • the cells were treated with 30 ⁇ M, 10 ⁇ M, 2 ⁇ M, 0.4 ⁇ M and 0.08 ⁇ M of the compounds of Examples 1 to 4, respectively, and cultured for 8 days. The medium containing the compound was added once again on the fourth day.
  • Sphere cell viability was assessed by Cell-titer Glo (Promega, WC, USA) and luciferase activity was detected using a Tecan plate reader (Biocompare, USA).
  • A2780 ovarian cancer cells were plated in 96-well plates at a density of 3000 viable cells per well and cultured in RPMI-1640 medium supplemented with 10% FBS, 1% penicillin / streptomycin Respectively. On the day following the incubation, the cells were treated with 100 ⁇ M, 30 ⁇ M, 10 ⁇ M, 3 ⁇ M and 0.3 ⁇ M of the compounds of Examples 1 to 4, respectively, and cultured for 3 days. Cell viability was assessed by Cell-titer Glo (Promega, WC, USA) and luciferase activity was detected using a Tecan plate reader (Biocompare, USA).
  • A2780-SP cells were plated in Ultra-Low Attachment round-bottomed 96-well corning at a viable cell density of 500 cells per well and cultured in cancer stem cell medium. On the day following the incubation, the cells were treated with 10 ⁇ M, 2 ⁇ M and 0.4 ⁇ M of the compounds of Examples 1 to 4, respectively, and cultured for 8 days at 37 ° C., 5% CO 2 and 95% humidity. Sphere size was analyzed using Image J software (NIH image).
  • A2780-SP cells were plated on Ultra-Low Attachment flat bottom 96-well corning at a viable cell density of 6000 cells per well and grown in cancer stem cell medium. The following day, the cells were treated with 10 ⁇ M of the compounds of Examples 1 to 4 and incubated for 60 hours at 37 ° C., 5% CO 2 and 95% humidity. Sphere forming confluence was analyzed using Incucyte (BioTek, VT, USA).
  • A2780-SP cells (ovarian cancer stem cells) were plated in Ultra-Low Attachment 6-well corning at 4 x 10 viable cell densities per well and cultured in cancer stem cell medium. The next day, the medium was replaced with Neuro Basal Medium (NBM), incubated for 16 hours in starvation, and treated with 10 ⁇ M of the compounds of Examples 1 to 4 for 1 hour. The medium was exchanged with a cancer stem cell medium containing the compound, and the cells were further cultured for 30 minutes before harvesting and dissolving in RiPA buffer. The extracted proteins were separated by SDS-PAGE gel and transferred to PVDF membranes for Western Blot analysis. After blocking with 5% skim milk, the membranes were incubated overnight with primary antibodies in blocking buffer at 4 ° C and then incubated with HRP-conjugated secondary antibody ( HRP-conjugated secondary antibodies).
  • HRP-conjugated secondary antibodies HRP-conjugated secondary antibodies
  • anti-phospho-AKT Ser473 (clone 193H12, Cell Signaling), anti-AKT (rabbit polyclonal, Cell Signaling), anti-phospho-ERK (Thr202 / Tyr204) monoclonal, Cell Signaling), anti-phospho-p38 (rabbit monoclonal, Cell Signaling), anti-p38 (rabbit monoclonal, Cell Signaling), anti-OCT3 / 4 (mouse monoclonal, Santa Cruz)
  • Anti-CD133 rabbit monoclonal, Abcam
  • anti-GAPDH mimouse monoclonal, Santa Cruz
  • anti-ALDH1 mimethyl-1
  • anti-SOX2 anti-SOX2 (rabbit monoclonal, Cell signaling).
  • the secondary antibodies used were as follows:
  • A2780-SP cells (ovarian cancer stem cells) were plated in Ultra-Low Attachment 6-well corning at a viable cell density of 1x10 6 cells per well and cultured in cancer stem cell medium. The following day, A2780-SP cells were treated with 10 ⁇ M of the compounds of Examples 1 to 4, cultured at 37 ° C, 5% CO 2, 95% humidity for 24 hours, and then harvested with a centrifuge. After washing once with PBS, the cells were resuspended in 0.3 ml of PBS. 0.7 ml of cold ethanol was slowly added dropwise to fix the cells, and the cells were incubated on ice for 1 hour.
  • Quantitative Real-time polymerase chain reaction Quantitative Real-time polymerase chain reaction
  • Trizol RNA extraction kit (Invitrogen) was used to extract the total RNA from the samples according to the manufacturer's instructions. 2 [mu] g of RNA was reverse transcribed with cDNA using the GoScriptTM cDNA synthesis system (GoScriptTM cDNA synthesis system, Promega). The synthesized cDNA was applied to Quantitative RT-PCR using FastStart SYBR green Master (Roche) and Bio-Rad S1000 Thermal cycler with indicated primers. GAPDH was used as a reference gene and the results were expressed relative to the control group using the ddCt method.
  • the composition of the external solution was 143 mM NaCl, 5.6 mM KCl, 10 mM CaCl 2 , 2 mM MgCl 2 , 10 mM HEPES, 5 mM glucose, 1 nM tetrodotoxin and 10 mM tetraethylammonium, The pH was adjusted to 7.4 using.
  • the composition of the internal pipette solution for the whole cell patch was 140 mM CsCl, 2 mM MgCl 2 , 3 mM Mg-ATP, 5 mM HEPES, 1.1 mM EGTA and pH was adjusted to 7.2 using CsOH .
  • the Ca 2+ current was measured using the Axopatch 700B, DigiData 1440A, pClamp 10.4 in a voltage clamp mode and after holding the basal membrane potential at -70 mV, starting at -70 mV and +10 mV The amount of current appearing while increasing the voltage was measured. After measuring the normal current, 10 ⁇ M of Manidipine of Example 3 was treated for 5 minutes, and the change in the amount of current was measured by applying the same voltage change. The access resistance (Ra) value of the whole cell patch clamp was 10 ⁇ 20 M ⁇ .
  • ovarian cancer stem cell line A2780-SP cells and ovarian cancer cell line A2780-AD cells were inoculated subcutaneously in nude mice 1x10 5 . At this time, ovarian cancer cells were inoculated on the left side of the nude mouse, and 8 ovarian cancer stem cells were inoculated on the right side. After the inoculation, the size of the tumor formation was measured from the 14th day.
  • control group (3 pBS treatment), Manidipine treatment group (3 animals -1 mpk treatment) Treatment group (3 animals -5mpk treatment), Manidipine and anti-cancer drug (Pacritaxel) treatment group were divided into two groups. Thereafter, drug administration and tumor size were measured at intervals of 3 to 4 days. After that, the animals were euthanized on the 31st day, and the weight and size of the tumors were finally measured.
  • cell viability analysis was carried out using the pharmaceutical compositions of Examples 1 to 4, 1 and 2, respectively.
  • the GI 50 values of the respective compounds were measured for each cell, and are shown in Table 3 below.
  • the specific experimental method is the same as the 1. cell viability assay of the above experimental protocol.
  • Figure 1 shows a dose-response curve of the viability of A2780-SP cells (ovarian cancer stem cells) when the example pharmaceutical composition is treated. , And the dose-response curve of the viability of A2780 cells (ovarian cancer cells).
  • Examples 1 to 4 were found to reduce the viability of A2780-SP cells, which are ovarian cancer cells in a dose-dependent manner.
  • the pharmaceutical compositions of Examples 1 to 4 were found to reduce the viability of A2780 cells, which are ovarian cancer cells, in a dose-dependent manner.
  • the pharmaceutical compositions of Examples 1 to 4 showed a GI50 value of 15 ⁇ M or less, thereby confirming that the cell growth inhibitory effect was excellent.
  • the lower the value of stem cells the more excellent selective growth inhibition effect is obtained in stem cells.
  • the pharmaceutical composition comprising the calcium channel inhibitor of the present invention shows the inhibitory effect on the growth of cancer stem cells, and thus it has anti-cancer effect.
  • the cell spheres of cancer stem cells were analyzed using the pharmaceutical compositions of Examples 1 to 4, 3.
  • the specific experimental method is the same as the 2. spherical analysis of the above experimental protocol.
  • FIG. 3 is an image showing the result of analyzing the sphere formation of A2780-SP cells (ovarian cancer stem cells) when the pharmaceutical composition of the Example was treated.
  • compositions of Examples 1 to 4 reduce the sphere formation of A2780-SP cells, which are ovarian cancer cells in a dose-dependent manner.
  • the sphere is a characteristic form of cancer stem cells, which means that the growth of the sphere is the growth of cancer stem cells. Therefore, the pharmaceutical composition containing the calcium channel inhibitor according to the present invention inhibits the formation of the stem cells of cancer stem cells, so that it has anti-cancer effect.
  • the cell spheres of cancer stem cells were analyzed using the pharmaceutical compositions of Examples 1 to 4, 4.
  • the specific experimental method is the same as that of Experimental Protocol.
  • FIG. 4 is a graph showing the results of measurement of the proliferation of A2780-SP cells by analyzing the sphere formation of A2780-SP cells (ovarian cancer stem cells) when the pharmaceutical composition of Example was treated.
  • the pharmaceutical compositions of Examples 1 to 4 inhibited sphere fusion, and showed a fusion rate of 1/3 or less as compared with the control group (DMSO treatment group) after 60 hours, Proliferation inhibitory effect can be shown.
  • the pharmaceutical composition comprising the calcium channel inhibitor according to the present invention inhibits the proliferation of cancer stem cells, and thus has anticancer effects.
  • FIG. 5 is an image showing changes in the expression of markers related to cancer stem cell function in A2780-SP cells (ovarian cancer stem cells) when the pharmaceutical composition of Example is treated.
  • Figure 6 is a graph quantifying the expression changes of markers related to cancer stem cell function in A2780-SP cells (ovarian cancer stem cells) when the example pharmaceutical composition is treated.
  • Example 1 bistyreine
  • Example 3 manidipine
  • Example 4 lomeligin
  • Example 2 reduces the expression of NANOG, SOX2, ALDH1, and CD133.
  • the pharmaceutical composition of the present invention can reduce the expression of the stem cells related to the stem cells of cancer stem cells which cause tolerance to existing anticancer drugs, and thus can be useful for cancer treatment.
  • FIG. 7 is an image showing changes in the activity of proteins involved in cancer stem cell survival and proliferation in A2780-SP cells (ovarian cancer stem cells) when the pharmaceutical composition of the Example was treated.
  • A2780-SP cells ovarian cancer stem cells
  • Example 1 bis(benidipine), Example 3 (manidipine), and Example 4 (lomeligin) was treated, the cancer stem cell survival and proliferation- The activity of AKT, ERK, and p38 was decreased.
  • Example 2 decreases the activity of ERK, p38.
  • the pharmaceutical composition of the present invention reduces the stem cell function of cancer stem cells, reduces the expression of proteins involved in cancer stem cell survival and proliferation, inhibits recurrence, metastasis, and progression of cancer, It can be useful for treatment.
  • Figure 9 is a graph showing the cell cycle changes of A2780-SP cells when the pharmaceutical composition of the example was treated.
  • Figure 10 is a graph showing the cell death of A2780-SP cells when the pharmaceutical composition of Example was treated. to be.
  • compositions of Examples 1 to 4 increase cell death of cancer stem cells.
  • the cell cycle of the cells can be analyzed by flow cytometry analysis.
  • the cell cycle of each cell is analyzed by flow cytometry, The number is expressed as a percentage.
  • the pharmaceutical composition of the present invention increases the apoptosis of cancer stem cells, and thus can be useful for the treatment of cancer.
  • Fig. 11 shows quantitative RT-PCR quantification of the expression levels of calcium channel subunits (Cacna1d, Cacna1f, Cacna1h) mRNA in A2780-SP cells and A2780 cells.
  • FIG. 13 shows the results of knockdown of calcium channel-related genes (si-Cacna1d, si-Cacna1f and si-Cacna1h) in A2780-SP cells and then to identify markers (OCT3 / 4, NANOG, SOX2, ALDH1 , CD133) was quantified by quantitative RT-PCR.
  • knockdown of a gene related to calcium channel in cancer stem cells revealed that the expression amount of mRNA of calcium channel subunit was remarkably decreased.
  • knockdown of genes related to calcium channels in cancer stem cells results in a decrease in mRNA expression of markers associated with cancer stem cells.
  • FIG. 14 is a graph showing the results of knockdown of calcium channel-related genes (si-Cacna1d, si-Cacna1f and si-Cacna1h) in A2780-SP cells, and stem cell-associated markers and the expression of proteins involved in the survival and proliferation of cancer stem cells.
  • FIG. 15 is a graph showing the results of knockdown of calcium channel-related genes (si-Cacna1d, si-Cacna1f, si-Cacna1h) in A2780-SP cells, a stem cell-associated marker, and a stem cell-associated marker and the expression of a protein associated with survival and proliferation of cancer stem cells.
  • Figure 16 is a graph showing that the amplitude of calcium current is reduced when the pharmaceutical composition of Example is treated with A2780-SP cells.
  • Example 3 which is a pharmaceutical composition containing the calcium channel inhibitor of the present invention, showed a larger amplitude of calcium current in ovarian cancer cell (A2780-SP) than ovarian cancer cell (A2780) -SP, the amplitude of the calcium current is remarkably suppressed.
  • the four pharmaceutical compositions of the present invention inhibit the cancer stem cell stem stem, which is a major factor in resistance to existing drugs through the inhibition of the calcium channel overexpressed in cancer stem cells, Suggesting that apoptosis may be induced.
  • cancer can be effectively used for cancer treatment by inhibiting recurrence, metastasis and progression of cancer.
  • FIG. 17 is a graph showing the results of measuring the cell survival rate of A2780-SP cells when the pharmaceutical composition of Example and cisplatin were used in combination.
  • FIG. 17 is a graph showing the results of measuring the cell survival rate of A2780-SP cells when the pharmaceutical composition of Example and cisplatin were used in combination.
  • Example 18 is a graph showing the results of analysis of cell proliferation of A2780-SP cells when the pharmaceutical composition of Example and cisplatin were used in combination.
  • the pharmaceutical composition containing the calcium channel inhibitor of the present invention when administered singly, it exhibits an excellent effect of reducing cell viability. However, when administered in combination with an anticancer agent, the cell viability of cancer stem cells is further reduced .
  • the pharmaceutical composition containing the calcium channel inhibitor of the present invention not only exhibits excellent anticancer effects even when used alone, but also can exhibit synergistic effects even higher when used in combination with existing anticancer drugs.
  • the cell viability was analyzed using the pharmaceutical compositions of Examples 1 to 4.
  • the results are shown in the following Table 5 Respectively.
  • the specific experimental method is the same as the 1. cell viability analysis of the above experimental protocol, and the normal cells were normal fibroblasts BJ6 and NIH-3T3.
  • the pharmaceutical compositions of Examples 1 to 4 exhibited cell viability of 80% or more, so that the pharmaceutical composition of the present invention had no effect on normal cells , And specifically shows cytotoxicity only to cancer cells, particularly cancer stem cells.
  • the pharmaceutical composition comprising the calcium channel inhibitor of the present invention does not affect normal cells, but exhibits an inhibitory effect on the growth of cancer stem cells.
  • the anticancer effect with less side effects can be exhibited.
  • the pharmaceutical composition containing the calcium channel inhibitor of the present invention is excellent in the effect of inhibiting the growth and proliferation of cancer stem cells even when used alone, As a result, it is possible to inhibit recurrence, metastasis and progression of cancer. Therefore, it can be used as a pharmaceutical composition or a combined preparation for cancer prevention or treatment.
  • FIG. 19 is a graph showing the results of tumorigenesis (A2780-AD) in the case of the ovarian cancer cell tumor animal model (A2780-AD) and the ovarian cancer stem cell tumor animal model (A2780-SP), alone or in combination with paclitaxel Inhibitory effect and evaluating the results.
  • the pharmaceutical composition containing the calcium channel inhibitor of the present invention can inhibit recurrence, metastasis and progression of ovarian cancer, and thus can be usefully used as a pharmaceutical composition for the prevention or treatment of ovarian cancer.
  • tablets were prepared by tableting according to a conventional method for producing tablets.
  • the capsules were filled in gelatin capsules according to the conventional preparation method of capsules.
  • an injectable preparation was prepared by incorporating the aforementioned components in the amounts indicated.
  • the ointment was prepared by incorporating the above ingredients in the prescribed amounts according to the usual preparation method of ointment.
  • Vitamin A acetate 70 mg
  • Vitamin E 1.0mg
  • Vitamin B6 0.5mg
  • Vitamin B12 0.2mg
  • composition ratio of the above-mentioned vitamin and mineral mixture is comparatively mixed with a component suitable for a health functional food as a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above components may be mixed , Granules may be prepared and used in the manufacture of a health functional food composition according to a conventional method.
  • the above components were mixed in accordance with a conventional health functional beverage manufacturing method, and the mixture was heated at 85 DEG C for about 1 hour with stirring, and the solution thus prepared was filtered to obtain a sterilized container, which was sealed and sterilized, Were used to prepare beverage compositions.
  • composition ratio is relatively mixed with the ingredient suitable for the favorite drink, it is also possible to arbitrarily modify the blending ratio according to the regional or national preference such as the demand class, demand country, use purpose, and the like.
  • the pharmaceutical composition containing the calcium channel inhibitor of the present invention can be usefully used as a pharmaceutical composition or a combined preparation for the prevention or treatment of cancer.

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Abstract

La présente invention concerne une composition pharmaceutique pour prévenir ou traiter le cancer contenant, en tant que substance active, un inhibiteur calcique ou un sel pharmaceutiquement acceptable de celui-ci. La composition pharmaceutique présente non seulement un excellent effet d'inhibition de la croissance et de la prolifération de cellules souches cancéreuses, même lorsqu'elle est utilisée seule, mais également un excellent effet pharmacologique lors de l'administration de la composition pharmaceutique conjointement avec des médicaments anticancéreux conventionnels. Étant donné qu'il est possible d'inhiber la récurrence, la métastase et la progression du cancer, la composition pharmaceutique peut utilement être utilisée en tant que composition pharmaceutique ou formulation combinée pour la prévention ou le traitement du cancer.
PCT/KR2019/001143 2018-01-26 2019-01-28 Composition pharmaceutique pour la prévention ou le traitement du cancer comprenant, en tant que substance active, un inhibiteur calcique ou un sel pharmaceutiquement acceptable de celui-ci WO2019147089A1 (fr)

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