WO2014119568A1 - UTILISATION D'INHIBITEUR DE LA HMG-CoA RÉDUCTASE POUR LE TRAITEMENT DE CANCERS RÉSISTANT AU CISPLATINE - Google Patents

UTILISATION D'INHIBITEUR DE LA HMG-CoA RÉDUCTASE POUR LE TRAITEMENT DE CANCERS RÉSISTANT AU CISPLATINE Download PDF

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WO2014119568A1
WO2014119568A1 PCT/JP2014/051833 JP2014051833W WO2014119568A1 WO 2014119568 A1 WO2014119568 A1 WO 2014119568A1 JP 2014051833 W JP2014051833 W JP 2014051833W WO 2014119568 A1 WO2014119568 A1 WO 2014119568A1
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cisplatin
cancer
hmg
coa reductase
resistant
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PCT/JP2014/051833
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Japanese (ja)
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公俊 河野
弘人 和泉
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学校法人産業医科大学
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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
    • A61K31/33—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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • 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
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • 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
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a cisplatin resistant cancer cytotoxic agent and a cisplatin resistant cancer therapeutic agent.
  • Pravastatin (trade name: mevalotin), simvastatin (trade name: Lipovas), etc. for drugs that lower cholesterol levels in blood by inhibiting the action of HMG-CoA reductase (also called statin inhibitors or statins)
  • statin inhibitors also called statin inhibitors or statins
  • Non-patent Document 2 In the group taking statins, it has been reported that the incidence of blood tumors is particularly low (Non-patent Document 2), while taking statins has no effect on reducing the risk of developing cancer.
  • Non-patent Document 3 has also been reported, and no consistent conclusion has been made about the effect of statin inhibiting cancer development. In addition, no report has been made on the anticancer activity of statins against drug-resistant cancer cells
  • Cisplatin is a first-line drug for the treatment of many malignant tumors, and is an anticancer agent that inhibits DNA synthesis by forming a cross-link in DNA through a special chemical reaction with chromosomal DNA.
  • cancer cells acquire cisplatin resistance by continuous administration of cisplatin.
  • an object of this invention is to provide the means for treatment of a cisplatin resistant cancer.
  • the present inventors have studied the antitumor effect of a HMG-CoA reductase inhibitor that lowers blood cholesterol level on cisplatin-resistant cancer cell lines.
  • simvastatin, lovastatin, compactin, fluvastatin It has been found that atorvastatin, pitavastatin and pravastatin all show higher cytotoxicity against cisplatin-resistant cancer cell lines than cisplatin-sensitive cancer cell lines.
  • the oxaliplatin resistant cancer cell line which is the same platinum preparation as cisplatin
  • the oxaliplatin resistant cancer cell line Since the cytotoxicity was not as high as that of the strain, it was found that the action of the HMG-CoA reductase inhibitor was specific to cisplatin-resistant cancer cells.
  • the present inventors have completed the present invention.
  • the present invention is as follows.
  • a cisplatin-resistant cancer cytotoxic agent comprising an HMG-CoA reductase inhibitor.
  • the HMG-CoA reductase inhibitor is at least one selected from the group consisting of simvastatin, lovastatin, compactin, fluvastatin, atorvastatin, pitavastatin, pravastatin, rosuvastatin and cerivastatin, and a pharmaceutically acceptable salt thereof.
  • the HMG-CoA reductase inhibitor is at least one selected from the group consisting of simvastatin, lovastatin, compactin, fluvastatin, atorvastatin, pitavastatin and pravastatin, and pharmaceutically acceptable salts thereof. [3 ]. [5] The agent according to any one of [1] to [4], wherein the cancer is prostate cancer or cervical cancer. [6] A cisplatin-resistant cancer therapeutic agent comprising an HMG-CoA reductase inhibitor. [7] The agent according to [6], wherein the active ingredient comprises an HMG-CoA reductase inhibitor.
  • a method for treating cisplatin-resistant cancer comprising administering an effective amount of an HMG-CoA reductase inhibitor to a subject.
  • An agent for use in injury of cisplatin-resistant cancer cells comprising an HMG-CoA reductase inhibitor.
  • Figure 2 shows the cytotoxicity of simvastatin against cisplatin sensitive and resistant cancer cell lines.
  • 2 shows the cytotoxicity of lovastatin against cisplatin sensitive and resistant cancer cell lines.
  • Figure 2 shows the cytotoxicity of compactin against cisplatin sensitive and resistant cancer cell lines.
  • Figure 5 shows cytotoxicity of fluvastatin sodium against cisplatin sensitive and resistant cancer cell lines.
  • Figure 3 shows the cytotoxicity of atorvastatin calcium against cisplatin sensitive and resistant cancer cell lines.
  • Figure 3 shows the cytotoxicity of pitavastatin calcium against cisplatin sensitive and resistant cancer cell lines.
  • Figure 3 shows the cytotoxicity of pravastatin sodium against cisplatin sensitive and resistant cancer cell lines.
  • Figure 5 shows the cytotoxicity of quercetin against cisplatin sensitive and resistant cancer cell lines.
  • Figure 3 shows the cytotoxicity of simvastatin against oxaliplatin sensitive and resistant cancer cell lines.
  • the vertical axis represents cell viability, and the horizontal axis represents simvastatin concentration ( ⁇ M).
  • Figure 3 shows the cytotoxicity of simvastatin against oxaliplatin sensitive and resistant cancer cell lines.
  • the vertical axis represents cell viability, and the horizontal axis represents simvastatin concentration ( ⁇ M).
  • the present invention provides a cisplatin-resistant cancer cytotoxic agent (hereinafter also referred to as the agent of the present invention) comprising an HMG-CoA reductase inhibitor.
  • HMG-CoA reductase inhibitors have been suggested to reduce the incidence of some cancers, but there are also negative reports, and their effects on inhibiting cancer However, it has not been proved. It was totally unpredictable that such HMG-CoA reductase inhibitors showed significant cytotoxicity against certain drug resistant cancer cell lines.
  • the present invention is based on the first discovery that an HMG-CoA reductase inhibitor unexpectedly shows stronger cytotoxicity against cisplatin-resistant cancer cell lines than cisplatin-sensitive cancer cell lines. is there.
  • an HMG-CoA reductase inhibitor refers to a substance having an activity of inhibiting ⁇ -hydroxy- ⁇ -methylglutaryl-CoA (HMG-CoA) reductase, which is a rate-limiting enzyme for cholesterol biosynthesis.
  • HMG-CoA ⁇ -hydroxy- ⁇ -methylglutaryl-CoA reductase
  • the activity of inhibiting HMG-CoA reductase is an activity measured based on the description in JP-A-5-25190, and specifically, it is measured by the following method.
  • HMG-CoA (0.05 ⁇ Ci)
  • crude HMG-CoA reductase enzyme 5 ⁇ l (7.5 ⁇ g protein), 20 mM NADPH, test substance, 100 mM phosphate buffer (pH 7.2), 10 Add mM imidazole, 5 mM dithiothreitol, and 10 mM EDTA to make 100 ⁇ l of the test solution.
  • Wistar rat liver microsome is used as a crude enzyme of HMG-CoA reductase.
  • the test solution is then incubated at 37 ° C. for 15 minutes to synthesize [ 14 C] mevalonic acid.
  • lovastatin which is a known HMG-CoA reductase inhibitor
  • lovastatin can be added to a final concentration of 100 nM to serve as an indicator of inhibitory activity. If the value obtained by correcting the radioactivity of the product with the radioactivity of the internal standard is significantly lower than that of the negative control without the addition of the test substance, the test substance is evaluated as having the activity of inhibiting HMG-CoA reductase can do.
  • the present invention is based on the finding of cisplatin-resistant cancer cell-specific cytotoxicity common to HMG-CoA reductase inhibitors known to date, as described below, and HMG-CoA A compound having an activity of inhibiting a reductase is expected to have similar cytotoxicity.
  • statins examples include all natural substances derived from microorganisms, semi-synthetic substances derived therefrom, and total synthetic compounds.
  • the HMG-CoA reductase inhibitor in the present invention is preferably simvastatin, lovastatin, compactin, fluvastatin, atorvastatin, pitavastatin and / or pravastatin.
  • the HMG-CoA reductase inhibitor may be in the form of a pharmaceutically acceptable salt.
  • Such pharmaceutically acceptable salts include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, and N, N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, Mention may be made of amines such as ethylenediamine, N-methylglucamine and procaine.
  • Alkali metal salts and alkaline earth metal salts are preferred.
  • fluvastatin and pravastatin are preferably used as sodium salts.
  • atorvastatin and pitavastatin are preferably used as calcium salts.
  • the HMG-CoA reductase inhibitor may be in an unsolvated form or a solvated form including a hydrate form.
  • the HMG-CoA reductase inhibitors used in the present invention may be used in combination of two or more at an appropriate ratio.
  • the HMG-CoA reductase inhibitor used in the present invention can be produced according to a method known per se.
  • Commercially available HMG-CoA reductase inhibitors may also be used, such as simvastatin (SIGMA S6196), lovastatin (WAKO 125-04581), compactin (WAKO 033-17301), fluvastatin sodium (WAKO 069-05571), Atorvastatin calcium (WAKO 012-23901), pitavastatin calcium (WAKO 012-23901), pravastatin sodium (WAKO 163-24861) and the like can be used.
  • cisplatin-resistant cancer is cancer (cells) acquired resistance to cisplatin.
  • Acquired resistant cancer refers to cancer (cells) that was initially sensitive to cisplatin but decreased in sensitivity as a result of continuing cisplatin treatment. The degree of sensitivity reduction is not particularly limited.
  • cancers that are not effective for treatment with chemotherapy using cisplatin eg, no decrease in tumor tissue volume or growth inhibition
  • acquired resistant cancer cells include cisplatin-resistant cancer cells derived from prostate cancer cell line PC3 cells, cisplatin-resistant cancer cell lines PCDP5 cells, and cervical cancer cell lines HeLa cells. Examples include cell line HCP4 cells, but are not limited thereto.
  • cancer may be any kind of cancer, and solid cancer [eg, gastrointestinal cancer (eg, stomach cancer, esophageal cancer, small intestine cancer, colon cancer, rectal cancer, anus Cancer, liver cancer, biliary tract cancer, pancreatic cancer, etc.), urological or genital cancer (eg, renal cancer, renal cell cancer, bladder cancer, prostate cancer, renal pelvis and ureteral cancer, gallbladder) Cancer, bile duct cancer, testicular cancer, penile cancer, uterine cancer, endometrial cancer, uterine sarcoma, cervical cancer, vaginal cancer, vulvar cancer, ovarian cancer, fallopian tube cancer, etc.
  • gastrointestinal cancer eg, stomach cancer, esophageal cancer, small intestine cancer, colon cancer, rectal cancer, anus Cancer, liver cancer, biliary tract cancer, pancreatic cancer, etc.
  • urological or genital cancer eg, renal cancer, renal cell cancer, bladder cancer, prostate cancer, renal
  • Brain / nervous cancer eg, brain tumor (glioblastoma, etc.), spinal cord tumor, etc.
  • head and neck cancer eg, laryngeal cancer, oral cancer, salivary gland cancer, sinus cancer, thyroid gland) Cancer
  • respiratory cancer eg, lung cancer (including small cell lung cancer, non-small cell lung cancer, metastatic lung cancer), bronchial cancer, etc.)
  • breast cancer Skin cancer eg, malignant melanoma
  • bone cancer eg, osteosarcoma, etc.
  • muscle cancer eg, rhabdomyosarcoma, etc.
  • blood cancer eg, myeloma, leukemia, etc. , Lymphoma, etc.
  • prostate cancer or cervical cancer preferably prostate cancer or cervical cancer.
  • the cisplatin resistant cancer cell is not particularly limited as long as it is a mammal-derived cell.
  • Mammals include, for example, rodents such as mice, rats, hamsters, guinea pigs, laboratory animals such as rabbits, pets such as dogs and cats, domestic animals such as cows, pigs, goats, horses and sheep, monkeys, orangutans and Examples include primates such as chimpanzees and humans, with humans being particularly preferred.
  • cytotoxicity means an action of reducing the survival rate of a target cell.
  • the survival rate can be measured by a method known per se. For example, in isolated cell lines, as shown in the examples described later, the water-soluble formazan dye is reduced by mitochondrial dehydrogenase. It can be measured by an assay using WST-8 converted to.
  • the cytotoxicity of the agent of the present invention is specific to cisplatin resistant cancer cells.
  • “Cisplatin-resistant cancer cell-specific cytotoxicity” is a stage in which cytotoxicity against cisplatin-resistant cancer cells is a parent strain of the cisplatin-resistant cancer cells and is acquired before cisplatin resistance is obtained by cisplatin treatment. It is stronger than the cytotoxicity against cisplatin-sensitive cancer cells.
  • the agent of the present invention Since the agent of the present invention has strong cytotoxicity against cisplatin-resistant cancer cells, it can be used for the treatment of cisplatin-resistant cancer. That is, the agent of the present invention can be used as a cisplatin resistant cancer therapeutic agent.
  • the administration target is a mammal having cisplatin resistant cancer.
  • cancer the above-mentioned cancer.
  • mammals include, for example, laboratory animals such as rodents and rabbits such as mice, rats, hamsters, and guinea pigs, domestic animals such as pigs, cows, goats, horses, sheep and minks, pets such as dogs and cats, humans, Primates such as monkeys, rhesus monkeys, marmosets, orangutans and chimpanzees.
  • the mammal is preferably a laboratory animal (eg mouse) or a primate (eg human), more preferably a human.
  • the dose of the agent of the present invention should be appropriately set according to the type of HMG-CoA reductase inhibitor that is the active ingredient, the route of administration, the animal species to be administered, the drug acceptability of the administration subject, body weight, age, etc. Can do.
  • the agent of the present invention can contain any carrier, for example, a pharmaceutically acceptable carrier, in addition to the HMG-CoA reductase inhibitor.
  • Examples of pharmaceutically acceptable carriers include sucrose, starch, mannitol, sorbit, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate, and other excipients, cellulose, methylcellulose, hydroxypropylcellulose, polypropylpyrrolidone.
  • Gelatin gum arabic, polyethylene glycol, sucrose, starch and other binders, starch, carboxymethylcellulose, hydroxypropyl starch, sodium-glycol starch, sodium bicarbonate, calcium phosphate, calcium citrate and other disintegrants, magnesium stearate , Aerosil, Talc, Lubricant such as sodium lauryl sulfate, Citric acid, Menthol, Glycyrrhizin / Ammonium salt, Glycine, Orange powder and other fragrances, Benzoic acid Preservatives such as thorium, sodium bisulfite, methylparaben, propylparaben, stabilizers such as citric acid, sodium citrate, acetic acid, suspensions such as methylcellulose, polyvinylpyrrolidone, aluminum stearate, dispersants such as surfactants, Examples include, but are not limited to, water, physiological saline, diluents such as orange juice, base waxes such as cacao butter,
  • Administration forms of the agent of the present invention include liquids, tablets, pills, drinking liquids, powders, suspensions, emulsions, granules, extracts, fine granules, syrups, soaking agents, decoctions, eye drops, and lozenges.
  • Patch, liniment, lotion, eye ointment, plaster, capsule, suppository, enema, injection (liquid, suspension, etc.), patch, ointment, jelly, pasta, inhalation Examples include agents, creams, sprays, nasal drops, aerosols and the like.
  • the agent of the present invention is administered by a method according to various forms when used.
  • an external preparation it is sprayed, affixed or applied directly to the required site such as the skin or mucous membrane, and in the case of tablets, pills, drinking solutions, suspensions, emulsions, granules and capsules, it is administered orally.
  • it is administered intravenously, intramuscularly, intradermally, subcutaneously, intraarticularly, intraperitoneally or intratumorally, and in the case of a suppository, it is administered intrarectally.
  • the content of the HMG-CoA reductase inhibitor in the pharmaceutical composition is not particularly limited and is appropriately selected over a wide range, and is, for example, about 0.01 to 100% by weight of the whole pharmaceutical composition.
  • the agent of the present invention may be used in combination with other anticancer agents.
  • anticancer agents include platinum preparations (eg, cisplatin, carboplatin, nedaplatin, oxaliplatin, etc.), alkylating agents (eg, nitrogen mustard, nitrogen mustard N-oxide, nitrogen mustard alkylating agents such as chlorambucil); Ethyleneimine derivatives such as carbocone and thiotepa; sulfonic acid esters such as busulfan and improsulfan tosylate; nitrosourea derivatives such as nimustine hydrochloride; and anticancer antibiotics (for example, mitomycin C, bleomycin, pepromycin, daunorubicin, Anthracycline antibiotic antitumor agents such as aclarubicin, adriamycin (doxorubicin), pirarubicin, THP-adriamycin, 4'-epidoxorubic
  • IC50 50% inhibitory concentration of cisplatin relating to the survival rate of PC3 cells, PCDP5 cells, HeLa cells and HCP4 cells.
  • PC3 1.92 ⁇ M
  • PCDP5 16.8 ⁇ M (8.8 times resistance)
  • HeLa 0.46 ⁇ M
  • HCP4 22.5 ⁇ M (49-fold resistance)
  • DLD1 cells and Caco2 cells were obtained from Professor Nobuhiko Kuwano of Kyushu University (currently a specially-appointed professor of the Faculty of Pharmaceutical Sciences of Kyushu University). The oxaliplatin resistant strain was prepared by the method described in Cancer Sci. 2011 Feb; 102 (2): 382-6.
  • PC3 cells and HeLa cells were seeded in a 96-well plate at 1,000 cells per well, and PCDP5 cells and HCP4 cells were seeded in a 96-well plate at 2,000 cells per well.
  • MEM Minimum Essential Medium
  • the 96-well plate was incubated in a humid atmosphere at 37 ° C. with 5% CO 2 concentration.
  • DLD1 cells and their oxaliplatin resistant strains, and Caco2 cells and their oxaliplatin resistant strains were cultured in the same manner as described above except that RPMI was used as a medium.
  • the culture medium is a medium in which the following drugs are added to the following maximum concentrations, a medium prepared by diluting this 1 to 9 times three times, or a medium containing no drug (each 100 ⁇ L) and further incubated for 72 hours.
  • Simvastatin SIGMA S6196
  • lovastatin WAKO 125-04581
  • compactin WAKO 033-17301
  • fluvastatin sodium WAKO 069-05571
  • atorvastatin calcium WAKO 012-23901
  • pitavastatin calcium WAKO 012-23901
  • Pravastatin sodium WAKO 163-24861
  • quercetin SIGMA Q4951
  • WST-8 assay was performed by the following procedure. After the medium in each well was removed by aspiration, 100 ⁇ L of TetraColor ONE (code number: 800560, Seikagaku Biobusiness Co., Ltd.) diluted 10-fold with the medium was added. After 2 to 4 hours, the absorbance (450 nm) was measured with a microplate reader (Bio-Rad model 550). Absorbance when TetraColor ONE was added to a well without cells was used as the background.
  • the 50% inhibitory concentration of lovastatin is reduced to about 530 times lower in cisplatin-resistant PCDP5 cells than in cisplatin-sensitive parental PC3 cells for prostate cancer cell lines, and cervical cancer cell lines
  • the concentration was reduced to about 1/29 of the cisplatin-sensitive parental HeLa cells.
  • the 50% inhibitory concentration of compactin is reduced to about 9 times lower in cisplatin-resistant PCDP5 cells than in cisplatin-sensitive parental PC3 cells for prostate cancer cell lines, and cervical cancer cell lines
  • the concentration was reduced to about 1/43 of the cisplatin-sensitive parental HeLa cells.
  • the 50% inhibitory concentration of fluvastatin sodium is reduced to about 11 times lower in cisplatin-resistant PCDP5 cells than in cisplatin-sensitive parental PC3 cells for prostate cancer cell lines, and cervical cancer
  • the concentration of cisplatin-resistant HCP4 cells was reduced to about 13 times that of the parent cisplatin-sensitive HeLa cell.
  • the 50% inhibitory concentration of atorvastatin calcium is reduced to about one-third for cisplatin-resistant PCDP5 cells compared to cisplatin-sensitive parental PC3 cells for prostate cancer cell lines, and cervical cancer cells
  • the concentration of cisplatin-resistant HCP4 cells was reduced to about 1/9 compared with the parent strain HeLa cells sensitive to cisplatin.
  • the 50% inhibitory concentration of pitavastatin calcium is reduced by about one-half for cisplatin-resistant PCDP5 cells compared to the cisplatin-sensitive parent PC3 cells for prostate cancer cell lines, and cervical cancer cells With respect to the strain, the concentration of cisplatin-resistant HCP4 cells was reduced to about 23-fold compared to the cisplatin-sensitive parent strain HeLa cells.
  • the 50% inhibitory concentration of pravastatin sodium is reduced to about one third of the cisplatin-resistant PCDP5 cells compared to the cisplatin-sensitive parental PC3 cells for prostate cancer cell lines, and cervical cancer cells
  • concentration of cisplatin-resistant HCP4 cells was reduced to about one-fifth compared to the parent strain HeLa cells sensitive to cisplatin.
  • quercetin which is not a statin inhibitor, did not show cytotoxicity specific to cisplatin-resistant cell lines. From the above results, it was shown that statins have a higher anticancer effect (cytotoxicity) on cisplatin-resistant cancer cell lines than on cisplatin-sensitive cancer cell lines.

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Abstract

La présente invention concerne un moyen pour le traitement de cancers résistant au cisplatine. La présente invention concerne, plus particulièrement, un agent cytotoxique du cancer résistant au cisplatine ou similaire, qui contient un inhibiteur de HMG-CoA réductase. La présente invention permet de détruire efficacement les cancers résistant au cisplatine, ce qui permet le traitement desdits cancers.
PCT/JP2014/051833 2013-01-29 2014-01-28 UTILISATION D'INHIBITEUR DE LA HMG-CoA RÉDUCTASE POUR LE TRAITEMENT DE CANCERS RÉSISTANT AU CISPLATINE WO2014119568A1 (fr)

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