WO2021241943A1 - Pharmaceutical composition for prevention or treatment of cancer - Google Patents

Pharmaceutical composition for prevention or treatment of cancer Download PDF

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Publication number
WO2021241943A1
WO2021241943A1 PCT/KR2021/006348 KR2021006348W WO2021241943A1 WO 2021241943 A1 WO2021241943 A1 WO 2021241943A1 KR 2021006348 W KR2021006348 W KR 2021006348W WO 2021241943 A1 WO2021241943 A1 WO 2021241943A1
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cancer
pharmaceutical composition
cisplatin
histone deacetylation
inhibitor
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PCT/KR2021/006348
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French (fr)
Korean (ko)
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박기청
김석모
임진홍
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연세대학교 산학협력단
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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • 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
    • 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 the prevention or treatment of cancer, and more particularly, to a pharmaceutical composition capable of inhibiting the growth of not only cancer cells, but also resistant cancer, recurrent cancer or metastatic cancer cell lines.
  • Cancer is one of the incurable diseases to be solved by civilization, and huge capital is being invested in development to cure it worldwide. and more than 60,000 people die.
  • carcinogens that cause cancer include smoking, ultraviolet rays, chemicals, food, and other environmental factors.
  • Substances currently used as therapeutic agents have considerable toxicity and cannot selectively remove only cancer cells, so there is an urgent need to develop an effective anticancer agent with less toxicity to prevent cancer as well as treatment after the onset of cancer. .
  • colorectal cancer is the third most common cancer worldwide and is one of the main causes of cancer-related diseases and mortality. Colorectal cancer accounts for 9.7% of all cancer incidence worldwide. In addition to 600,000 colorectal cancer-related deaths, there are over 1 million cases of colorectal cancer diagnosed each year. Although surgery and chemotherapy are performed to improve clinical outcomes, many colorectal cancer patients appear to have tumor metastases to advanced stages with low survival rates. Therefore, there is a need for a new treatment regimen in preparing an effective treatment strategy for colorectal cancer.
  • One object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer.
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating resistant cancer, recurrent cancer, or metastatic cancer.
  • Another object of the present invention is to provide a pharmaceutical composition for inhibiting the growth of cancer stem cells.
  • a pharmaceutical composition for preventing or treating cancer comprising a histone deacetylation inhibitor (HDAC inhibitor) and cisplatin as active ingredients.
  • HDAC inhibitor histone deacetylation inhibitor
  • the "histone deacetylation inhibitor” inhibits the activity of histone deacetylase (HDAC), which is known to play an important role in gene expression regulation mechanisms, and histone hyperacetylation (Hypoacetylation) and inducing changes in gene expression accordingly.
  • HDAC histone deacetylase
  • the histone deacetylation inhibitor is a) a domain capable of binding to a metal (particularly zinc), b) a linker capable of filling the channel of the histone deacetylase, and c) a histone deacetylase It has structural features of a surface recognition region that can interact with structures at the edge of the active region (J. Med. Chem., 2003, 46(24), 5097-5116).
  • N-hydroxy-7-(2-naphthylthio)heptanomide represented by the following formula (1) or its It may be a pharmaceutically acceptable salt:
  • N-hydroxy-7-(2-naphthylthio)heptanamide represented by Formula 1 is called 'HNHA' and is a cell permeability inhibitor of histone deacetylase (HDAC) activity, It inhibits cell cycle progression and induces histone hyperacetylation and p21 transcription.
  • HNHA inhibits tumor growth, inhibits growth of human umbilical vein endothelial cells (HUVECs), and inhibits tube formation and migration of HUVECs.
  • HDAC histone deacetylase
  • the pharmaceutically acceptable salts are salts generally considered by those skilled in the art to be suitable for medical applications (eg, since such salts are not harmful to the subject to be treated with the salts), or each salts that cause acceptable side effects within the treatment of
  • the pharmaceutically acceptable salt is a salt considered acceptable by a regulatory authority such as the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or the Pharmaceutical and Medical Devices Agency (PMDA) of the Ministry of Health, Labor and Welfare of Japan. .
  • the present invention in principle provides an intermediate, for example in the preparation of a compound according to the invention or a physiologically functional derivative thereof, or a pharmaceutically acceptable salt of a compound according to the invention or a physiologically functional derivative thereof
  • an intermediate for example in the preparation of a compound according to the invention or a physiologically functional derivative thereof, or a pharmaceutically acceptable salt of a compound according to the invention or a physiologically functional derivative thereof
  • salts of the compounds according to the invention which are not themselves pharmaceutically acceptable.
  • Said salts include water-insoluble salts, particularly water-soluble salts.
  • a particular compound according to the invention or a physiologically functional derivative thereof is capable of forming salts, ie whether said compound according to the invention or a physiologically functional derivative thereof is, for example, For example, it can be easily determined whether or not a group has a chargeable group such as an amino group, a carboxylic acid group, and the like.
  • Exemplary salts of the compounds of the present invention are acid addition salts or salts with bases, particularly pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases commonly used in pharmaceuticals, which are water-insoluble or particularly water-soluble acid addition salts. is salt Depending on the substituents of the compounds of the present invention, salts with bases may also be suitable.
  • Acid addition salts can be prepared, for example, by combining a solution of a compound of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. It can be formed by mixing.
  • pharmaceutically acceptable base addition salts include alkali metal salts (eg, sodium or potassium salts); alkaline earth metal salts (eg, calcium or magnesium salts); and salts formed with suitable organic ligands (eg, ammonium, quaternary ammonium and amines formed with counter anions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyl sulfonates and aryl sulfonates). cations) may be included.
  • alkali metal salts eg, sodium or potassium salts
  • alkaline earth metal salts eg, calcium or magnesium salts
  • suitable organic ligands eg, ammonium, quaternary ammonium and amines formed with counter anions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyl sulfonates and aryl sulfonates
  • Illustrative examples of pharmaceutically acceptable salts include acetate, adipate, alginate, arginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, Bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, ethanesulfonate, Formate, fumarate, galactate, galacturonate, gluconate, glutamate, glycerophosphate, hemisulphate, heptanoate, hexanoate, hexylresorcinate, hydrobromide, hydrochloride, hydroiodide , 2-hydroxy-ethanesulfonate, hydroxynaphthoate
  • Salts which are not pharmaceutically acceptable in the present invention and which, for example, can be obtained as process products during the preparation of the compounds according to the invention on an industrial scale, are also included in the invention and, if desired, are known to the person skilled in the art. It can be converted into a pharmaceutically acceptable salt by a method.
  • the histone deacetylation inhibitor may be included in the composition at a concentration of 1 ⁇ M to 20 ⁇ M.
  • concentration of the histone deacetylation inhibitor is less than 1 ⁇ M, the effect of the composition may not be sufficiently exhibited, and when the concentration of the histone deacetylation inhibitor exceeds 20 ⁇ M, the toxicity of the composition to normal cells may increase, but this It is not limited.
  • the cisplatin is one of the alkylating agents widely used in cancer treatment, and is a compound in which two chlorines and ammonia are coordinated to a platinum atom (cis-diamminedichloroplatinum (II)[Pt(NH 3 ) 2 Cl 2 ]), the cis structure is known to prevent cell division by forming a chelate ring with DNA.
  • cisplatin itself has been classified as a class 2A carcinogen by the International Agency for Research on Cancer, there is a problem in that it is difficult to use in high concentrations.
  • the cisplatin may be included in the composition at a concentration of 10 ⁇ M to 200 ⁇ M.
  • concentration of cisplatin is less than 10 ⁇ M, the effect of the composition may not be sufficiently exhibited, and when the concentration of cisplatin exceeds 200 ⁇ M, toxicity of the composition to normal cells may increase, but is not limited thereto.
  • the histone deacetylation inhibitor and the cisplatin may be included in a molar ratio of 1:1 to 100 in the composition, and when the molar ratio of the histone deacetylation inhibitor to the cisplatin is included in the above range, a low dose is used. It may produce an effective synergistic effect in the treatment of cancer, but is not limited thereto.
  • the term "cancer” refers to or refers to a physiological condition characterized by unregulated cell growth typically in mammals.
  • the type of cancer to be prevented or treated is not particularly limited, but for example, breast cancer, biliary tract cancer, gallbladder cancer, pancreatic cancer, colorectal cancer, uterine cancer, esophageal cancer, stomach cancer, brain cancer, rectal cancer, lung cancer, It may be one or more cancers selected from the group consisting of bladder cancer, kidney cancer, ovarian cancer, prostate cancer, uterine cancer, head and neck cancer, skin cancer, blood cancer, and liver cancer, preferably colon cancer.
  • a pharmaceutical composition for preventing or treating resistant cancer, recurrent cancer, or metastatic cancer comprising a histone deacetylation inhibitor (HDAC inhibitor) and cisplatin as active ingredients .
  • HDAC inhibitor histone deacetylation inhibitor
  • the histone deacetylation inhibitor is N-hydroxy-7-(2-naphthylthio)heptanomide represented by Formula 1 or its It may be a pharmaceutically acceptable salt.
  • the histone deacetylation inhibitor may be included in the composition at a concentration of 1 ⁇ M to 20 ⁇ M.
  • concentration of the histone deacetylation inhibitor is less than 1 ⁇ M, the effect of the composition may not be sufficiently exhibited, and when the concentration of the histone deacetylation inhibitor exceeds 20 ⁇ M, the toxicity of the composition to normal cells may increase, but this It is not limited.
  • the cisplatin may be included in the composition at a concentration of 10 ⁇ M to 200 ⁇ M.
  • concentration of cisplatin is less than 10 ⁇ M, the effect of the composition may not be sufficiently exhibited, and when the concentration of cisplatin exceeds 200 ⁇ M, toxicity of the composition to normal cells may increase, but is not limited thereto.
  • the histone deacetylation inhibitor and the cisplatin may be included in a molar ratio of 1:1 to 100 in the composition, and when the molar ratio of the histone deacetylation inhibitor to the cisplatin is included in the above range, a low dose is used. It may produce an effective synergistic effect in the treatment of cancer, but is not limited thereto.
  • the development of drug resistance is prevented or previously generated resistance is prevented.
  • can be overcome to enhance sensitivity to anticancer drugs can also prevent cancer recurrence or treat recurrent cancer, prevent cancer metastasis from primary cancer to other organs or tissues, or metastasize cancer can be treated
  • resistant cancer refers to a cancer that is a drug for cancer treatment, in particular, exhibits extremely low sensitivity to anticancer drug treatment, and does not show improvement, alleviation, alleviation, or treatment symptoms by the treatment.
  • the resistant cancer may have resistance to a specific treatment from the beginning, and did not initially show resistance, but may occur because it no longer exhibits sensitivity to the same treatment due to genetic mutation in cancer cells due to long-term treatment.
  • cancer treatment drug refers to a drug for treating cancer, and may be an anticancer drug, and the type is not particularly limited, but may preferably be a drug for the treatment of colorectal cancer.
  • nitrogen mustard imatinib, oxaliplatin, rituximab, erlotinib, neratinib, lapatinib, gefitinib, vandetanib, nirotinib, semasanib, bosutinib, axitinib, cediranib , restaurtinib, trastuzumab, gefitinib, bortezomib, sunitinib, carboplatin, sorafenib, bevacizumab, cisplatin, cetuximab, viscumalbum, asparaginase, tretinoin, hydroxycarba amide, dasatinib, estramustine, gemtuzumab
  • the term "overcoming resistance” refers to an action of increasing the sensitivity of cancer cells that have acquired resistance to a specific drug to a drug for treatment.
  • the specific drug refers to a drug for treating cancer, particularly an anticancer drug.
  • the increase in sensitivity refers to the extent to which the concentration exhibiting effects such as growth inhibition and apoptosis of cancer cells that have acquired resistance is equal to or higher than the concentration exhibiting effects such as growth inhibition for non-resistant cancer cells.
  • means to reach Synonyms with overcoming the tolerance include "resistance suppression", “resistance release”, “resistance release” and "sensitivity enhancement".
  • recurrence of cancer means that cancer cannot be detected after chemotherapy, for example, surgical resection, radiotherapy, or chemotherapy, but is found again after a certain period of time.
  • the “recurrent cancer” refers to a cancer resulting from cancer recurrence as described above.
  • recurrent colorectal cancer occurs with a probability of about 30-50% after colorectal cancer treatment, and more than 60% occurs within 2 years after the first colorectal cancer treatment, and the remaining 40% occurs within 2 to 5 years. may recur later.
  • resection is often difficult, and even if resection is possible, a large-scale operation may be inevitable.
  • the term “metastasis” refers to the property of cancer to move to another place separated by distance from a primary organ or part.
  • the "metastatic cancer” is a cancer having the property to metastasize or a cancer that has metastasized.
  • the metastatic cancer may metastasize to the liver, lung, bone, lymph node or abdominal cavity, but is not limited thereto.
  • the metastatic cancer is difficult to treat, and in particular, metastatic colorectal cancer, whose primary cancer is colorectal cancer, is difficult to operate except for a small portion of metastatic colorectal cancer that has metastasized to the liver, and the progression and treatment may be more complicated than the initial treatment process.
  • the cancer is breast cancer, biliary tract cancer, gallbladder cancer, pancreatic cancer, colon cancer, uterine cancer, esophageal cancer, stomach cancer, brain cancer, rectal cancer, lung cancer, bladder cancer, kidney cancer, ovarian cancer, prostate cancer, uterine cancer, head and neck cancer according to the site of occurrence in the present invention , may be skin cancer, blood cancer, liver cancer, etc., preferably colon cancer, but is not limited thereto.
  • cancer stem cells Cancer Stem Cell, Tumor Initiating Cells; CSC, TICs
  • HDAC inhibitor histone deacetylation inhibitor
  • cisplatin a histone deacetylation inhibitor
  • the histone deacetylation inhibitor is N-hydroxy-7-(2-naphthylthio)heptanomide represented by Formula 1 or its It may be a pharmaceutically acceptable salt.
  • the histone deacetylation inhibitor may be included in the composition at a concentration of 1 ⁇ M to 20 ⁇ M.
  • concentration of HNHA is less than 1 ⁇ M, the effect of the composition may not be sufficiently exhibited, and when the concentration of HNHA exceeds 20 ⁇ M, toxicity of the composition to normal cells may increase, but is not limited thereto.
  • the cisplatin may be included in the composition at a concentration of 10 ⁇ M to 200 ⁇ M.
  • concentration of cisplatin is less than 10 ⁇ M, the effect of the composition may not be sufficiently exhibited, and when the concentration of cisplatin exceeds 200 ⁇ M, toxicity of the composition to normal cells may increase, but is not limited thereto.
  • the histone deacetylation inhibitor and the cisplatin may be included in a molar ratio of 1:1 to 100 in the composition, and when the molar ratio of the histone deacetylation inhibitor to the cisplatin is included in the above range, a low dose is used. It may produce an effective synergistic effect in the treatment of cancer, but is not limited thereto.
  • the cancer is breast cancer, biliary tract cancer, gallbladder cancer, pancreatic cancer, colorectal cancer, uterine cancer, esophageal cancer, stomach cancer, brain cancer, rectal cancer, lung cancer, bladder cancer, kidney cancer, ovarian cancer, prostate cancer, uterine cancer, head and neck cancer, skin cancer, blood cancer
  • it may be one or more cancers selected from the group consisting of liver cancer, preferably colon cancer, and if the cancer progression such as tumor differentiation and/or proliferation is a cancer stem cell-dependent type of cancer described in the present invention It is not limited thereto.
  • the cancer stem cells (Cancer Stem CELL, Tumor Initiating Cells; CSC, TICs) are present in about 1 to 2% in the malignant tumor tissue and are different from the self-renewal ability (self-renewal) characteristic of normal stem cells. It has been reported that although it has pluripotent ability to differentiate into malignant tumors, it has an abnormal self-regulatory function.
  • cancer stem cells were discovered by Bonnet and Dick in 1997 by isolating a subset of leukocytes expressing CD34 without expressing the surface marker CD38 (Blood, 1997). Since then, evidence has been presented that cancer stem cells are present in breast cancer (PNAS, 2003), brain tumors (Nature, 2004), prostate cancer (Cancer Res, 2005), colorectal cancer (Nature, 2007), and melanoma (Nature, 2008). has become A small number of cancer stem cells contained in tumors has emerged as a major cause of tumor malignancy, anticancer resistance, and recurrence.
  • Cancer stem cells have markers that distinguish them from other cancer cells, and various cancer stem cell markers specific to cancer are known as cancer stem cell markers as shown in Table 1 below. have.
  • the cancer stem cells described above constantly self-renew, can make tumors with a small number of less than one thousand cells in an experimental animal model, and have the ability as malignant tumor cells.
  • chemotherapy and radiation therapy which are cancer treatments
  • the removal of cancer stem cells is increasingly recognized as a barometer that can measure the success or failure of cancer treatment.
  • cancer can recur from the remaining cancer stem cells if all cancer stem cells are not killed even if cancer cells are killed using various existing treatment methods such as surgery, radiation therapy, and chemotherapy.
  • interest is growing in chemotherapy targeting cancer stem cells having the ability to regenerate tumors and developing a treatment protocol for treating cancer based on the chemotherapy.
  • cancer stem cells in normal tissues regulate cell growth and differentiation by a self-renewal mechanism, but cancer stem cells are affected by tumor microenvironmental factors around tumor cells, resulting in abnormal self-renewal and It is suggested that by activating the maintenance pathway and rapidly integrating, it becomes malignant, acquires resistance to chemotherapy, and ultimately causes cancer recurrence.
  • a detailed study of the mechanism of interaction with the entity of the tumor microenvironmental factors that control the accumulation and maintenance of cancer stem cells has not yet been conducted.
  • the cancer stem cells that are the target of growth inhibition may include all of the above-listed cancer stem cells, but may particularly be colorectal cancer stem cells.
  • inhibiting growth of cancer stem cells may include the meaning of inhibiting cancer stem cell maintenance, inhibiting cancer stem cell malignance, and inhibiting cancer stem cell invasive activity.
  • prevention may include, without limitation, any action that blocks cancer symptoms or suppresses or delays cancer symptoms using the pharmaceutical composition of the present invention.
  • treatment may include, without limitation, any action in which cancer symptoms are improved or beneficial by examining the pharmaceutical composition of the present invention.
  • the pharmaceutical composition may be characterized in the form of capsules, tablets, granules, injections, ointments, powders or drinks, and the pharmaceutical composition may be characterized in that it is targeted to humans.
  • the pharmaceutical composition of the present invention is not limited thereto, but each can be formulated in the form of oral dosage forms such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories, and sterile injection solutions according to conventional methods.
  • the pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers may include binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, dyes, fragrances, etc. for oral administration, and in the case of injections, buffers, preservatives, pain-freezing agents A topical agent, solubilizer, isotonic agent, stabilizer, etc.
  • the dosage form of the pharmaceutical composition of the present invention can be prepared in various ways by mixing with a pharmaceutically acceptable carrier as described above.
  • a pharmaceutically acceptable carrier as described above.
  • it can be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and in the case of injections, it can be prepared in the form of unit dose ampoules or multiple doses. have.
  • it can be formulated as a solution, suspension, tablet, capsule, sustained release formulation, and the like.
  • suitable carriers, excipients and diluents for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil may be used.
  • it may further include a filler, an anti-agglomeration agent, a lubricant, a wetting agent, a flavoring agent, an emulsifier, a preservative, and the like.
  • the route of administration of the pharmaceutical composition according to the present invention is not limited thereto, but oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical , sublingual or rectal. Oral or parenteral administration is preferred.
  • parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • the pharmaceutical composition of the present invention may also be administered in the form of a suppository for rectal administration.
  • the pharmaceutical composition of the present invention depends on several factors including the activity of the specific compound used, age, weight, general health, sex, formula, administration time, administration route, excretion rate, drug formulation, and the severity of the specific disease to be prevented or treated.
  • the dosage of the pharmaceutical composition may vary depending on the patient's condition, weight, disease severity, drug form, administration route and period, but may be appropriately selected by those skilled in the art, and 0.0001 to 50 mg/day kg or 0.001 to 50 mg/kg. Administration may be administered once a day, or may be administered in several divided doses. The above dosage does not limit the scope of the present invention in any way.
  • the pharmaceutical composition according to the present invention may be formulated as pills, dragees, capsules, solutions, gels, syrups, slurries, and suspensions.
  • a method for preventing or treating cancer comprising administering an effective amount of a histone deacetylation inhibitor (HDAC inhibitor) and cisplatin to an individual in need of administration.
  • HDAC inhibitor histone deacetylation inhibitor
  • the histone deacetylation inhibitor is N-hydroxy-7-(2-naphthylthio)heptanomide represented by Formula 1 or its It may be a pharmaceutically acceptable salt.
  • the histone deacetylation inhibitor may be administered at a concentration of 1 ⁇ M to 20 ⁇ M, and when the concentration of the histone deacetylation inhibitor is less than 1 ⁇ M, the effect of the composition may not be sufficiently exhibited, and the histone deacetylation inhibitor If the concentration of is more than 20 ⁇ M, the toxicity to normal cells may increase, but is not limited thereto.
  • the cisplatin may be administered at a concentration of 10 ⁇ M to 200 ⁇ M, and when the concentration of cisplatin is less than 10 ⁇ M, the effect of the composition may not be sufficiently exhibited.
  • the toxicity of the composition may increase, but is not limited thereto.
  • the histone deacetylation inhibitor and the cisplatin may be administered in a molar ratio of 1:1 to 100, and when the molar ratio of the histone deacetylation inhibitor and the cisplatin is included in the above range, cancer treatment with a low dose can produce an effective synergistic effect, but is not limited thereto.
  • the histone deacetylation inhibitor and the cisplatin may be administered simultaneously, separately, or sequentially, and the order of administration of the two drugs is not particularly limited.
  • the cancer is breast cancer, biliary tract cancer, gallbladder cancer, pancreatic cancer, colon cancer, uterine cancer, esophageal cancer, stomach cancer, brain cancer, rectal cancer, lung cancer, bladder cancer, kidney cancer, ovarian cancer, prostate cancer, uterine cancer, head and neck cancer according to the site of occurrence in the present invention , may be skin cancer, blood cancer, liver cancer, etc., preferably colon cancer, but is not limited thereto.
  • prevention of resistant cancer, recurrent cancer or metastatic cancer comprising administering an effective amount of a histone deacetylation inhibitor (HDAC inhibitor) and cisplatin to an individual in need of administration or to a method of treatment.
  • HDAC inhibitor histone deacetylation inhibitor
  • the histone deacetylation inhibitor is N-hydroxy-7-(2-naphthylthio)heptanomide represented by Formula 1 or its It may be a pharmaceutically acceptable salt.
  • the histone deacetylation inhibitor may be administered at a concentration of 1 ⁇ M to 20 ⁇ M, and when the concentration of the histone deacetylation inhibitor is less than 1 ⁇ M, the effect of the composition may not be sufficiently exhibited, and the histone deacetylation inhibitor If the concentration of is more than 20 ⁇ M, the toxicity to normal cells may increase, but is not limited thereto.
  • the cisplatin may be administered at a concentration of 10 ⁇ M to 200 ⁇ M, and when the concentration of cisplatin is less than 10 ⁇ M, the effect of the composition may not be sufficiently exhibited.
  • the toxicity of the composition may increase, but is not limited thereto.
  • the histone deacetylation inhibitor and the cisplatin may be administered in a molar ratio of 1:1 to 100, and when the molar ratio of the histone deacetylation inhibitor and the cisplatin is included in the above range, cancer treatment with a low dose can produce an effective synergistic effect, but is not limited thereto.
  • the histone deacetylation inhibitor and the cisplatin may be administered simultaneously, separately, or sequentially, and the order of administration of the two drugs is not particularly limited.
  • the resistant cancer is a cancer having resistance to a drug for cancer treatment, particularly an anticancer drug
  • the type of the anticancer agent is not particularly limited, but may preferably be a drug for the treatment of colorectal cancer.
  • Specific examples include nitrogen mustard, imatinib, oxaliplatin, rituximab, erlotinib, neratinib, lapatinib, gefitinib, vandetanib, nirotinib, semasanib, bosutinib, axitinib, cediranib , restaurtinib, trastuzumab, gefitinib, bortezomib, sunitinib, carboplatin, sorafenib, bevacizumab, cisplatin, cetuximab, viscumalbum, asparaginase, tretinoin, hydroxycarba amide, dasatinib, estramustine, gem
  • the cancer is breast cancer, biliary tract cancer, gallbladder cancer, pancreatic cancer, colon cancer, uterine cancer, esophageal cancer, stomach cancer, brain cancer, rectal cancer, lung cancer, bladder cancer, kidney cancer, ovarian cancer, prostate cancer, uterine cancer, head and neck cancer according to the site of occurrence in the present invention , may be skin cancer, blood cancer, liver cancer, etc., preferably colon cancer, but is not limited thereto.
  • growth inhibition of cancer stem cells comprising administering an effective amount of a histone deacetylation inhibitor (HDAC inhibitor) and cisplatin to an individual in need of administration it's about how
  • the histone deacetylation inhibitor is N-hydroxy-7-(2-naphthylthio)heptanomide represented by Formula 1 or its It may be a pharmaceutically acceptable salt.
  • the histone deacetylation inhibitor may be administered at a concentration of 1 ⁇ M to 20 ⁇ M, and when the concentration of the histone deacetylation inhibitor is less than 1 ⁇ M, the effect of the composition may not be sufficiently exhibited, and the histone deacetylation inhibitor If the concentration of is more than 20 ⁇ M, the toxicity to normal cells may increase, but is not limited thereto.
  • the cisplatin may be administered at a concentration of 10 ⁇ M to 200 ⁇ M, and when the concentration of cisplatin is less than 10 ⁇ M, the effect of the composition may not be sufficiently exhibited.
  • the toxicity of the composition may increase, but is not limited thereto.
  • the histone deacetylation inhibitor and the cisplatin may be administered in a molar ratio of 1:1 to 100, and when the molar ratio of the histone deacetylation inhibitor and the cisplatin is included in the above range, cancer treatment with a low dose can produce an effective synergistic effect, but is not limited thereto.
  • the histone deacetylation inhibitor and the cisplatin may be administered simultaneously, separately, or sequentially, and the order of administration of the two drugs is not particularly limited.
  • the cancer is breast cancer, biliary tract cancer, gallbladder cancer, pancreatic cancer, colon cancer, uterine cancer, esophageal cancer, stomach cancer, brain cancer, rectal cancer, lung cancer, bladder cancer, kidney cancer, ovarian cancer, prostate cancer, uterine cancer, head and neck cancer according to the site of occurrence in the present invention , may be skin cancer, blood cancer, liver cancer, etc., preferably colon cancer, but is not limited thereto.
  • the dose, schedule, and route of administration of the histone deacetylation inhibitor and cisplatin may be determined according to the size and condition of the individual and according to standard pharmaceutical practice.
  • exemplary routes of administration include intravenous, intraarterial, intraperitoneal, intrapulmonary, intravascular, intramuscular, intratracheal, subcutaneous, intraocular, intrathecal, or transdermal.
  • the dose administered to a subject may vary depending, for example, on the particular type of active ingredient administered, the route of administration, and the particular type and stage of the disease being treated.
  • the amount should be sufficient to produce a desired response, such as a therapeutic response to the disease, without severe toxicity or adverse events.
  • the amount of active ingredient is at least about 10%, 20%, 30%, 40% compared to the corresponding disease in the same subject prior to treatment, or compared to the corresponding activity in another subject not receiving treatment. , 50%, 60%, 70%, 80%, 90%, 95% or 100% in an amount sufficient to reduce the progression of the disease, ameliorate the disease, or treat the disease.
  • Standard methods such as in vitro assays with purified enzymes, cell-based assays, animal models or human experiments can be used to measure the magnitude of the effect.
  • the pharmaceutical composition according to the present invention can prevent or treat cancer by effectively inhibiting the proliferation of cancer cells or cancer stem cells by using a histone deacetylation inhibitor and cisplatin together, and further preventing or preventing drug resistance from occurring Alternatively, it is possible to increase the sensitivity to anticancer drugs by overcoming the previously generated resistance, and, in addition, prevent cancer recurrence or metastasis of cancer from the primary cancer to other organs or tissues, or effectively treat relapsed or metastasized cancer can be treated
  • FIG. 1 is a graph showing the number of cells when cisplatin and HNHA alone or a mixture thereof is treated in HT-29 colorectal cancer cell line according to an embodiment of the present invention.
  • FIG. 2 is a graph showing the number of cells in the case of treatment with cisplatin and HNHA alone or a mixture thereof in the recurrent colorectal cancer cell line according to an embodiment of the present invention.
  • FIG. 3 is a graph showing the number of cells when treated with cisplatin and HNHA alone or a mixture thereof in a metastatic colorectal cancer cell line according to an embodiment of the present invention.
  • HDAC inhibitor histone deacetylation inhibitor
  • N-hydroxy-7-(2-naphthylthio)heptanomide N-hydroxy-7- (2-naphthylthio)heptanomide
  • pharmaceutically acceptable salt thereof preferably as a pharmaceutical composition for preventing or treating cancer comprising cisplatin as an active ingredient.
  • HDAC inhibitor preferably N-hydroxy-7-(2-naphthylthio)heptanomide (N-hydroxy-7-(2-naphthylthio) ) heptanomide) or a pharmaceutically acceptable salt thereof; And it relates to a pharmaceutical composition for preventing or treating resistant cancer, recurrent cancer, or metastatic cancer comprising cisplatin as an active ingredient.
  • HDAC inhibitor preferably N-hydroxy-7-(2-naphthylthio)heptanomide (N-hydroxy-7-(2-naphthylthio) ) heptanomide) or a pharmaceutically acceptable salt thereof;
  • a pharmaceutical composition for inhibiting the growth of cancer stem cells comprising cisplatin as an active ingredient.
  • YUMC-C1 and YUMC-C2 cells which are colon cancer cell lines, were obtained through the following procedure.
  • the tumor mass was obtained during surgical resection of the primary site and metastasis site of colorectal cancer.
  • the tumor mass obtained the day after resection was stored in physiological saline containing antifungal and antibiotics, and then moved to the laboratory. After removing normal tissue and fat from the tumor mass, the tumor tissue was washed with 1X HBSS. Tumor tissue was triturated with dissociation medium in tubes.
  • dissociation medium DMEM/F12 containing 1 mg/ml of collagenase type IV (Sigma, USA) and 20% FBS was used.
  • the crushed and suspended tumor cells were washed with 50ml 1X HBSS, filtered with a sterile 70-micropore nylon cell strainer (BD Falcom), and centrifuged at 1400 rpm for 5 minutes.
  • Cells were resuspended in RPMI-1640 (Hyclone) medium containing 10% fetal bovine serum (Hyclone, South Logan, UT, USA) and 2% penicillin/streptomycin solution (Gibco, Grand Island, NY, USA). Cell viability was measured by trypan blue staining exclusion method.
  • the colorectal cancer cell line HT-29 used as a control (2) YUMC-C1, a recurrent colorectal cancer cell line derived from a patient, and (3) YUMC-C2 cells, a metastatic colorectal cancer cell line derived from a patient After each separation, cultured in RPMI-1640 medium containing 10% fetal bovine serum.
  • colorectal cancer cell line HT-29 used as a control (2) YUMC-C1, a recurrent colorectal cancer cell line derived from a patient, (3) cisplatin and YUMC-C2 cells, a metastatic colorectal cancer cell line derived from a patient
  • HT-29, YUMC-C1, and YUMC-C2 cells were treated with HNHA, cisplatin, or these in combination, and then IC 50 was measured by MTT assay. were measured and the results are shown in Table 3 below.
  • colorectal cancer cell line HT-29 used as a control (2) YUMC-C1, a recurrent colorectal cancer cell line derived from a patient, (3) metastatic colorectal cancer cell line derived from a patient
  • IC 50 when cisplatin and HNHA were administered in combination, IC 50 was significantly lower than when cisplatin was administered alone or when HNHA was administered alone.
  • colorectal cancer cell line HT-29 used as a control (2) YUMC-C1, a recurrent colorectal cancer cell line derived from a patient, (3) cisplatin and YUMC-C2 cells, a metastatic colorectal cancer cell line derived from a patient
  • HNHA; cisplatin; lenvatinib co-administration of cisplatin and HNHA (Cisplatin+HNHA; C+H)
  • HNHA cisplatin+HNHA; C+H
  • YUMC-C1 cells a recurrent colorectal cancer cell line derived from a patient
  • HNHA or cisplatin alone they were treated in combination (C+H). It was confirmed that the number of cells in the cell line was significantly reduced, and the effect of reducing the number of cells in the recurrent colorectal cancer cell line was lower than that of lenvatinib alone or combined treatment with lenvatinib and HNHA (L+H). It was confirmed that it was remarkably excellent.
  • the combination of cisplatin and HNHA according to the present invention can be used as an effective therapeutic agent for colorectal cancer, particularly anticancer drug-resistant colorectal cancer, recurrent colorectal cancer, or metastatic colorectal cancer.
  • the present invention relates to a pharmaceutical composition for the prevention or treatment of cancer, and more particularly, to a pharmaceutical composition capable of inhibiting the growth of not only cancer cells, but also resistant cancer, recurrent cancer or metastatic cancer cell lines.

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Abstract

The present invention relates to a pharmaceutical composition for prevention or treatment of cancer and, more specifically, to a pharmaceutical composition comprising a histone deacetylation (HDAC) inhibitor and cisplatin as active ingredients. The pharmaceutical composition according to the present invention effectively inhibits the proliferation of cancer cells or cancer stem cells by using both a histone deacetylation inhibitor and cisplatin, thereby preventing or treating cancer as well as preventing resistance to an anticancer drug, and the metastasis or recurrence of cancer.

Description

암의 예방 또는 치료용 약학적 조성물Pharmaceutical composition for preventing or treating cancer
본 발명은 암의 예방 또는 치료용 약학적 조성물에 관한 것으로, 보다 상세하게는 암 세포 뿐만 아니라, 내성 암, 재발성 암 또는 전이성 암 세포주의 성장을 억제할 수 있는 약학적 조성물에 관한 것이다. The present invention relates to a pharmaceutical composition for the prevention or treatment of cancer, and more particularly, to a pharmaceutical composition capable of inhibiting the growth of not only cancer cells, but also resistant cancer, recurrent cancer or metastatic cancer cell lines.
암은 인류가 해결해야 할 난치병 중의 하나로, 전 세계적으로 이를 치유하기 위한 개발에 막대한 자본이 투자되고 있는 실정이며, 우리나라의 경우, 질병 사망원인 중 제1위의 질병으로서 연간 약 10만명 이상이 진단되고, 약 6만명 이상이 사망하고 있다. Cancer is one of the incurable diseases to be solved by mankind, and huge capital is being invested in development to cure it worldwide. and more than 60,000 people die.
이러한 암의 유발 인자인 발암물질로는 흡연, 자외선, 화학물질, 음식물, 기타 환경인자들이 있으나, 그 유발 원인이 다양하여 치료제의 개발이 어려울 뿐만 아니라 발생하는 부위에 따라 치료제의 효과 또한 각기 다르다. 현재 치료제로 사용되는 물질들은 상당한 독성을 지니고 있으며, 암 세포만을 선택적으로 제거하지 못하므로, 암의 발생 후 이의 치료뿐 아니라, 암의 발생을 예방하기 위한 독성이 적고 효과적인 항암제의 개발이 절실히 필요하다.Examples of carcinogens that cause cancer include smoking, ultraviolet rays, chemicals, food, and other environmental factors. Substances currently used as therapeutic agents have considerable toxicity and cannot selectively remove only cancer cells, so there is an urgent need to develop an effective anticancer agent with less toxicity to prevent cancer as well as treatment after the onset of cancer. .
한편, 대장암(Colorectal cancer; CRC)은 전 세계적으로 세 번째로 가장 일반적인 암이며, 암-관련 질병 및 사망률의 주요 원인 중 하나이다. 모든 암 발생률 중 대장암은 전 세계적으로 9.7%를 차지한다. 육십만 명의 대장암 관련 사망뿐만 아니라 매년 백만 명 이상의 대장암 진단 사례가 있다. 임상 결과를 개선하기 위해 수술과 화학요법이 수행되나, 많은 대장암 환자들은 낮은 생존율을 갖는 진행 병기로의 종양 전이를 갖는 것으로 나타난다. 그러므로, 대장암의 효과적인 치료 전략을 마련함에 있어 새로운 치료 요법이 필요하다.Meanwhile, colorectal cancer (CRC) is the third most common cancer worldwide and is one of the main causes of cancer-related diseases and mortality. Colorectal cancer accounts for 9.7% of all cancer incidence worldwide. In addition to 600,000 colorectal cancer-related deaths, there are over 1 million cases of colorectal cancer diagnosed each year. Although surgery and chemotherapy are performed to improve clinical outcomes, many colorectal cancer patients appear to have tumor metastases to advanced stages with low survival rates. Therefore, there is a need for a new treatment regimen in preparing an effective treatment strategy for colorectal cancer.
본 발명의 일 목적은 암 예방 또는 치료용 약학적 조성물을 제공하는 것을 목적으로 한다.One object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer.
본 발명의 다른 목적은 내성 암, 재발성 암 또는 전이성 암의 예방 또는 치료용 약학적 조성물을 제공하는 것을 목적으로 한다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating resistant cancer, recurrent cancer, or metastatic cancer.
본 발명의 다른 일 목적은 암 줄기세포의 성장 억제용 약학적 조성물을 제공하는 것을 목적으로 한다.Another object of the present invention is to provide a pharmaceutical composition for inhibiting the growth of cancer stem cells.
그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당업계에서 통상의 지식을 가진 자에게 명확하게 이해될 수 있을 것이다. However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problems, and other problems not mentioned will be clearly understood by those of ordinary skill in the art from the following description.
본 발명의 일 구현 예에 따르면, 히스톤 탈아세틸화 저해제(Histone Deacetylation inhibitor; HDAC inhibitor) 및 시스플라틴(Cisplatin)을 유효 성분으로 포함하는 암의 예방 또는 치료용 약학적 조성물에 관한 것이다. According to one embodiment of the present invention, it relates to a pharmaceutical composition for preventing or treating cancer comprising a histone deacetylation inhibitor (HDAC inhibitor) and cisplatin as active ingredients.
본 발명에서 상기 "히스톤 탈아세틸화 저해제"는 유전자 발현 조절 기작에 중요한 역할을 하는 것으로 알려져 있는 히스톤 탈아세틸화 효소(Histone deacetylase; HDAC)의 활성을 저해하는 것으로, 히스톤의 과아세틸화(Hypoacetylation)와 이에 따른 유전자 발현의 변화를 유도한다. 상기 히스톤 탈아세틸화 저해제는 a) 금속(특히, 아연)과 결합 가능한 영역(domain), b) 상기 히스톤 탈아세틸화 효소의 채널을 채울 수 있는 링커(linker), 및 c) 히스톤 탈아세틸화 효소 활성 영역의 가장자리에서 구조체들과 상호 작용할 수 있는 표면 인지 영역의 구조적인 특징을 갖고 있다(J. Med. Chem., 2003, 46(24), 5097-5116). 본 발명에서 상기 히스톤 탈아세틸화 저해제로는 하기 화학식 1로 표시되는 N-하이드록시-7-(2-나프틸티오)헵타노마이드(N-hydroxy-7-(2-naphthylthio)heptanomide) 또는 이의 약학적으로 허용되는 염일 수 있다:In the present invention, the "histone deacetylation inhibitor" inhibits the activity of histone deacetylase (HDAC), which is known to play an important role in gene expression regulation mechanisms, and histone hyperacetylation (Hypoacetylation) and inducing changes in gene expression accordingly. The histone deacetylation inhibitor is a) a domain capable of binding to a metal (particularly zinc), b) a linker capable of filling the channel of the histone deacetylase, and c) a histone deacetylase It has structural features of a surface recognition region that can interact with structures at the edge of the active region (J. Med. Chem., 2003, 46(24), 5097-5116). In the present invention, as the histone deacetylation inhibitor, N-hydroxy-7-(2-naphthylthio)heptanomide represented by the following formula (1) or its It may be a pharmaceutically acceptable salt:
[화학식 1][Formula 1]
Figure PCTKR2021006348-appb-I000001
Figure PCTKR2021006348-appb-I000001
본 발명에서 상기 화학식 1로 표시되는 N-하이드록시-7-(2-나프틸티오)헵타노마이드는 'HNHA'라고 불리우며, 히스톤 디아세틸라제(histone deacetylase, HDAC) 활성의 세포 투과성 억제제로, 세포 주기의 진행을 억제하며 히스톤 하이퍼아세틸화(histone hyperacetylation) 및 p21 전사를 유도한다. HNHA는 종양 성장을 억제하며, 인간 제대 정맥 내피 세포(human umbilical vein endothelial cells; HUVECs)의 성장을 억제하고, 튜브 형성과 HUVECs의 이동을 억제한다. In the present invention, N-hydroxy-7-(2-naphthylthio)heptanamide represented by Formula 1 is called 'HNHA' and is a cell permeability inhibitor of histone deacetylase (HDAC) activity, It inhibits cell cycle progression and induces histone hyperacetylation and p21 transcription. HNHA inhibits tumor growth, inhibits growth of human umbilical vein endothelial cells (HUVECs), and inhibits tube formation and migration of HUVECs.
본 발명에서 상기 약학적으로 허용되는 염은, 의학적 적용에 적합한 것으로 당업자에 의해 일반적으로 간주되는 염(예를 들어 이러한 염이 상기 염으로 치료될 수 있는 대상체에게 유해하지 않기 때문임), 또는 각각의 치료 내에서 허용 가능한 부작용을 야기하는 염이다. 일반적으로, 상기 약학적으로 허용되는 염은 미국 식품 의약국(FDA), 유럽 의약청(EMA), 또는 일본 후생성의 의약품 의료기기 종합기구(PMDA)와 같은 규제 당국에 의해 허용되는 것으로 간주되는 염이다. 그러나, 본 발명은 원칙적으로, 예를 들어 본 발명에 따른 화합물 또는 그의 생리학적으로 작용성인 유도체의 제조에서의 중간체, 또는 본 발명에 따른 화합물의 약학적으로 허용되는 염 또는 그의 생리학적으로 작용성인 유도체의 제조에서의 중간체로서, 그 자체로는 약학적으로 허용되지 않는 본 발명에 따른 화합물의 염을 또한 포함한다. 상기 염은 수불용성 염을 포함하고, 특히, 수용성 염을 포함한다.In the present invention, the pharmaceutically acceptable salts are salts generally considered by those skilled in the art to be suitable for medical applications (eg, since such salts are not harmful to the subject to be treated with the salts), or each salts that cause acceptable side effects within the treatment of In general, the pharmaceutically acceptable salt is a salt considered acceptable by a regulatory authority such as the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or the Pharmaceutical and Medical Devices Agency (PMDA) of the Ministry of Health, Labor and Welfare of Japan. . However, the present invention in principle provides an intermediate, for example in the preparation of a compound according to the invention or a physiologically functional derivative thereof, or a pharmaceutically acceptable salt of a compound according to the invention or a physiologically functional derivative thereof Also included as intermediates in the preparation of derivatives are salts of the compounds according to the invention which are not themselves pharmaceutically acceptable. Said salts include water-insoluble salts, particularly water-soluble salts.
각각의 경우에, 당업자는 본 발명에 따른 특정 화합물 또는 그의 생리학적으로 작용성인 유도체가 염을 형성할 수 있는지 여부, 즉, 상기 본 발명에 따른 화합물 또는 그의 생리학적으로 작용성인 유도체가, 예를 들어 아미노 기, 카르복실산 기 등과 같은 전하를 띨 수 있는 기를 가지는지 여부를 쉽게 결정할 수 있다.In each case, the person skilled in the art will know whether a particular compound according to the invention or a physiologically functional derivative thereof is capable of forming salts, ie whether said compound according to the invention or a physiologically functional derivative thereof is, for example, For example, it can be easily determined whether or not a group has a chargeable group such as an amino group, a carboxylic acid group, and the like.
본 발명의 화합물의 예시적인 염은 산 부가 염 또는 염기와의 염, 특히 약학적으로 허용되는 무기산 및 유기산 부가 염 및 약학에서 통상적으로 사용되는 염기와의 염이며, 이는 수불용성 또는 특히 수용성 산 부가 염이다. 본 발명의 화합물의 치환기에 따라 염기와의 염이 또한 적합할 수 있다. 산 부가 염은, 예를 들어, 본 발명의 화합물의 용액을 염산, 황산, 푸마르산, 말레산, 석신산, 아세트산, 벤조산, 시트르산, 타르타르산, 탄산 또는 인산과 같은 약학적으로 허용되는 산의 용액과 혼합함으로써 형성될 수 있다. 마찬가지로, 약학적으로 허용되는 염기 부가 염은 알칼리 금속염(예를 들어, 나트륨 또는 칼륨 염); 알칼리 토금속 염(예를 들어, 칼슘 또는 마그네슘 염); 및 적합한 유기 리간드로 형성된 염(예를 들어, 할라이드, 하이드록사이드, 카복실레이트, 설페이트, 포스페이트, 니트레이트, 알킬 설포네이트 및 아릴 설포네이트와 같은 반대 음이온을 사용하여 형성된 암모늄, 4차 암모늄 및 아민 양이온)을 포함할 수 있다. 약학적으로 허용되는 염의 예시적인 예로는 아세테이트, 아디페이트, 알기네이트, 아르기네이트, 아스코르베이트, 아스파테이트, 벤젠설포네이트, 벤조에이트, 바이카르보네이트, 바이설페이트, 바이타르트레이트, 보레이트, 브로마이드, 부티레이트, 칼슘 에데테이트, 캄포레이트, 캄포설포네이트, 캄실레이트, 카르보네이트, 클로라이드, 시트레이트, 디글루코네이트, 디하이드로클로라이드, 도데실설페이트, 에데테이트, 에디실레이트, 에탄설포네이트, 포르메이트, 푸마레이트, 갈락테이트, 갈락투로네이트, 글루코네이트, 글루타메이트, 글리세로포스페이트, 헤미설페이트, 헵타노에이트, 헥사노에이트, 헥실레소르시네이트, 하이드로브로마이드, 하이드로클로라이드, 하이드로요오다이드, 2-하이드록시-에탄설포네이트, 하이드록시나프토에이트, 요오다이드, 이소부티레이트, 이소티오네이트, 락테이트, 라우레이트, 라우릴 설페이트, 말레이트, 말레에이트, 말로네이트, 만델레이트, 메탄설포네이트(메실레이트), 메틸설페이트, 2-나프탈렌설포네이트, 니코티네이트, 니트레이트, 올레에이트, 옥살레이트, 팔미테이트, 판토테네이트, 펙티네이트, 퍼설페이트, 3-페닐프로피오네이트, 포스페이트/디포스페이트, 프탈레이트, 피크레이트, 피발레이트, 폴리갈락투로네이트, 프로피오네이트, 살리실레이트, 스테아레이트, 설페이트, 수베레이트, 석시네이트, 탄네이트, 타르트레이트, 토실레이트, 운데카노에이트, 발레레이트 등이 포함되지만 이로 한정되지 않는다.Exemplary salts of the compounds of the present invention are acid addition salts or salts with bases, particularly pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases commonly used in pharmaceuticals, which are water-insoluble or particularly water-soluble acid addition salts. is salt Depending on the substituents of the compounds of the present invention, salts with bases may also be suitable. Acid addition salts can be prepared, for example, by combining a solution of a compound of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. It can be formed by mixing. Likewise, pharmaceutically acceptable base addition salts include alkali metal salts (eg, sodium or potassium salts); alkaline earth metal salts (eg, calcium or magnesium salts); and salts formed with suitable organic ligands (eg, ammonium, quaternary ammonium and amines formed with counter anions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyl sulfonates and aryl sulfonates). cations) may be included. Illustrative examples of pharmaceutically acceptable salts include acetate, adipate, alginate, arginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, Bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, ethanesulfonate, Formate, fumarate, galactate, galacturonate, gluconate, glutamate, glycerophosphate, hemisulphate, heptanoate, hexanoate, hexylresorcinate, hydrobromide, hydrochloride, hydroiodide , 2-hydroxy-ethanesulfonate, hydroxynaphthoate, iodide, isobutyrate, isothionate, lactate, laurate, lauryl sulfate, maleate, maleate, malonate, mandelate, methane Sulfonate (mesylate), methylsulfate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate /diphosphate, phthalate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, suberate, succinate, tannate, tartrate, tosylate, undecanoate, Valerate and the like are included, but are not limited thereto.
본 발명에서 약학적으로 허용되지 않으며, 예를 들어, 산업적 규모로 본 발명에 따른 화합물을 제조하는 동안 공정 생성물로서 수득될 수 있는 염이 또한 본 발명에 포함되고, 요망되는 경우, 이는 당업자에게 알려진 방법에 의해 약학적으로 허용되는 염으로 전환될 수 있다.Salts which are not pharmaceutically acceptable in the present invention and which, for example, can be obtained as process products during the preparation of the compounds according to the invention on an industrial scale, are also included in the invention and, if desired, are known to the person skilled in the art. It can be converted into a pharmaceutically acceptable salt by a method.
본 발명에서, 상기 히스톤 탈아세틸화 저해제는 상기 조성물 내에 1μM 내지 20μM 농도로 포함될 수 있다. 상기 히스톤 탈아세틸화 저해제의 농도가 1μM 미만인 경우 조성물의 효과가 충분하게 나타나지 않을 수 있고, 상기 히스톤 탈아세틸화 저해제의 농도가 20μM를 초과하는 경우 정상 세포에 대한 조성물의 독성이 커질 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the histone deacetylation inhibitor may be included in the composition at a concentration of 1 μM to 20 μM. When the concentration of the histone deacetylation inhibitor is less than 1 μM, the effect of the composition may not be sufficiently exhibited, and when the concentration of the histone deacetylation inhibitor exceeds 20 μM, the toxicity of the composition to normal cells may increase, but this It is not limited.
본 발명에서, 상기 시스플라틴은 암 치료에 널리 사용되는 알킬화제 가운데 하나로, 백금 원자에 2개의 염소와 암모니아가 배위된 화합물로(시스-다이암민다이클로로백금(II)[Pt(NH3)2Cl2]), 시스구조가 DNA와 킬레이트 고리를 형성하여 세포분열을 막는 것으로 알려져 있다. 하지만, 시스플라틴은 그 자체가 국제 암 연구소에 의하여 2A등급 발암물질로 분류된 바 있어, 고농도로 사용되기 어려운 문제점이 있다.In the present invention, the cisplatin is one of the alkylating agents widely used in cancer treatment, and is a compound in which two chlorines and ammonia are coordinated to a platinum atom (cis-diamminedichloroplatinum (II)[Pt(NH 3 ) 2 Cl 2 ]), the cis structure is known to prevent cell division by forming a chelate ring with DNA. However, since cisplatin itself has been classified as a class 2A carcinogen by the International Agency for Research on Cancer, there is a problem in that it is difficult to use in high concentrations.
본 발명에서, 상기 시스플라틴은 상기 조성물 내에 10μM 내지 200μM 농도로 포함될 수 있다. 상기 시스플라틴의 농도가 10μM 미만인 경우 조성물의 효과가 충분하게 나타나지 않을 수 있고, 상기 시스플라틴의 농도가 200μM를 초과하는 경우 정상세포에 대한 조성물의 독성이 커질 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the cisplatin may be included in the composition at a concentration of 10 μM to 200 μM. When the concentration of cisplatin is less than 10 μM, the effect of the composition may not be sufficiently exhibited, and when the concentration of cisplatin exceeds 200 μM, toxicity of the composition to normal cells may increase, but is not limited thereto.
또한, 본 발명에서 상기 히스톤 탈아세틸화 저해제와 상기 시스플라틴은 상기 조성물 내에 1:1~100의 몰비로 포함될 수 있고, 상기 히스톤 탈아세틸화 저해제와 상기 시스플라틴의 몰비가 상기한 범위로 포함될 경우 저용량으로 암 치료에 효과적인 시너지 효과를 낼 수 있으나, 이에 제한되는 것은 아니다.In addition, in the present invention, the histone deacetylation inhibitor and the cisplatin may be included in a molar ratio of 1:1 to 100 in the composition, and when the molar ratio of the histone deacetylation inhibitor to the cisplatin is included in the above range, a low dose is used. It may produce an effective synergistic effect in the treatment of cancer, but is not limited thereto.
본 발명에서 상기 "암"은 포유류에서 전형적으로 조절되지 않는 세포 성장으로 특징지어진 생리적 상태를 나타내거나 가리킨다. 본 발명의 상기 암은 예방 또는 치료의 대상이 되는 암의 종류는 특별히 제한하지 않으나, 예를 들면, 유방암, 담도암, 담낭암, 췌장암, 대장암, 자궁암, 식도암, 위암, 뇌암, 직장암, 폐암, 방광암, 신장암, 난소암, 전립선암, 자궁암, 두경부암, 피부암, 혈액암 및 간암으로 이루어진 군으로부터 선택되는 1종 이상의 암일 수 있고, 바람직하게는 대장암일 수 있다. In the present invention, the term "cancer" refers to or refers to a physiological condition characterized by unregulated cell growth typically in mammals. For the cancer of the present invention, the type of cancer to be prevented or treated is not particularly limited, but for example, breast cancer, biliary tract cancer, gallbladder cancer, pancreatic cancer, colorectal cancer, uterine cancer, esophageal cancer, stomach cancer, brain cancer, rectal cancer, lung cancer, It may be one or more cancers selected from the group consisting of bladder cancer, kidney cancer, ovarian cancer, prostate cancer, uterine cancer, head and neck cancer, skin cancer, blood cancer, and liver cancer, preferably colon cancer.
본 발명의 또 다른 구현 예에 따르면, 히스톤 탈아세틸화 저해제(HDAC inhibitor) 및 시스플라틴(Cisplatin)을 유효 성분으로 포함하는 내성 암, 재발성 암 또는 전이성 암의 예방 또는 치료용 약학적 조성물에 관한 것이다.According to another embodiment of the present invention, it relates to a pharmaceutical composition for preventing or treating resistant cancer, recurrent cancer, or metastatic cancer comprising a histone deacetylation inhibitor (HDAC inhibitor) and cisplatin as active ingredients .
본 발명에서 상기 히스톤 탈아세틸화 저해제로는 상기 화학식 1로 표시되는 N-하이드록시-7-(2-나프틸티오)헵타노마이드(N-hydroxy-7-(2-naphthylthio)heptanomide) 또는 이의 약학적으로 허용되는 염일 수 있다.In the present invention, the histone deacetylation inhibitor is N-hydroxy-7-(2-naphthylthio)heptanomide represented by Formula 1 or its It may be a pharmaceutically acceptable salt.
본 발명에서, 상기 히스톤 탈아세틸화 저해제는 상기 조성물 내에 1μM 내지 20μM 농도로 포함될 수 있다. 상기 히스톤 탈아세틸화 저해제의 농도가 1μM 미만인 경우 조성물의 효과가 충분하게 나타나지 않을 수 있고, 상기 히스톤 탈아세틸화 저해제의 농도가 20μM를 초과하는 경우 정상세포에 대한 조성물의 독성이 커질 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the histone deacetylation inhibitor may be included in the composition at a concentration of 1 μM to 20 μM. When the concentration of the histone deacetylation inhibitor is less than 1 μM, the effect of the composition may not be sufficiently exhibited, and when the concentration of the histone deacetylation inhibitor exceeds 20 μM, the toxicity of the composition to normal cells may increase, but this It is not limited.
본 발명에서, 상기 시스플라틴은 상기 조성물 내에 10μM 내지 200μM의 농도로 포함될 수 있다. 상기 시스플라틴의 농도가 10μM 미만인 경우 조성물의 효과가 충분하게 나타나지 않을 수 있고, 상기 시스플라틴의 농도가 200μM를 초과하는 경우 정상세포에 대한 조성물의 독성이 커질 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the cisplatin may be included in the composition at a concentration of 10 μM to 200 μM. When the concentration of cisplatin is less than 10 μM, the effect of the composition may not be sufficiently exhibited, and when the concentration of cisplatin exceeds 200 μM, toxicity of the composition to normal cells may increase, but is not limited thereto.
또한, 본 발명에서 상기 히스톤 탈아세틸화 저해제와 상기 시스플라틴은 상기 조성물 내에 1:1~100의 몰비로 포함될 수 있고, 상기 히스톤 탈아세틸화 저해제와 상기 시스플라틴의 몰비가 상기한 범위로 포함될 경우 저용량으로 암 치료에 효과적인 시너지 효과를 낼 수 있으나, 이에 제한되는 것은 아니다.In addition, in the present invention, the histone deacetylation inhibitor and the cisplatin may be included in a molar ratio of 1:1 to 100 in the composition, and when the molar ratio of the histone deacetylation inhibitor to the cisplatin is included in the above range, a low dose is used. It may produce an effective synergistic effect in the treatment of cancer, but is not limited thereto.
본 발명에서는 상기 히스톤 탈아세틸화 저해제 중에서도 특히 N-하이드록시-7-(2-나프틸티오)헵타노마이드와, 시스플라틴을 병용 투여할 경우, 약제의 내성이 생기는 것을 방지하거나 혹은 기 생성된 내성을 극복하여 항암제에 대한 감수성을 증진시킬 수 있고, 그 외에도 암의 재발을 예방하거나, 재발된 암을 치료할 수 있으며, 원발암에서 타 기관이나 조직으로의 암이 전이하는 것을 예방하거나, 전이된 암을 치료할 수 있다.In the present invention, among the above histone deacetylation inhibitors, in particular, when N-hydroxy-7-(2-naphthylthio)heptanomide and cisplatin are co-administered, the development of drug resistance is prevented or previously generated resistance is prevented. can be overcome to enhance sensitivity to anticancer drugs, can also prevent cancer recurrence or treat recurrent cancer, prevent cancer metastasis from primary cancer to other organs or tissues, or metastasize cancer can be treated
본 발명에서 상기 "내성 암"이란, 암 치료용 약물로, 특히 항암제 치료에 대하여 극히 낮은 감수성을 나타내어, 상기 치료법에 의해 증세가 호전, 완화, 경감 또는 치료증상을 나타내지 않는 암을 의미한다. 상기 내성 암은 특정한 치료법에 대하여 처음부터 내성을 가질 수도 있고, 최초에는 내성을 나타내지 않았으나, 긴 시간의 치료로 인하여 암 세포 내의 유전자 변이 등에 의하여 동일한 치료에 대해 더이상 감수성을 나타내지 않게 되어 발생할 수도 있다. In the present invention, the term "resistant cancer" refers to a cancer that is a drug for cancer treatment, in particular, exhibits extremely low sensitivity to anticancer drug treatment, and does not show improvement, alleviation, alleviation, or treatment symptoms by the treatment. The resistant cancer may have resistance to a specific treatment from the beginning, and did not initially show resistance, but may occur because it no longer exhibits sensitivity to the same treatment due to genetic mutation in cancer cells due to long-term treatment.
본 발명에서 "암 치료용 약물"이란 암을 치료하기 위한 약물로, 항암제일 수 있고, 그 종류를 특별히 한정하지는 않으나, 바람직하게는 대장암의 치료용 약물일 수 있다. 구체적인 예를 들면, 나이트로젠 머스타드, 이마티닙, 옥살리플라틴, 리툭시맙, 엘로티닙, 네라티닙, 라파티닙, 제피티닙, 반데타닙, 니로티닙, 세마사닙, 보수티닙, 악시티닙, 세디라닙, 레스타우르티닙, 트라스투주맙, 게피티니브, 보르테조밉, 수니티닙, 카보플라틴, 소라페닙, 베바시주맙, 시스플라틴, 세툭시맙, 비스쿰알붐, 아스파라기나제, 트레티노인, 하이드록시카바마이드, 다사티닙, 에스트라머스틴, 겜투주맵오조가마이신, 이브리투모맙튜세탄, 헵타플라틴, 메칠아미노레불린산, 암사크린, 알렘투주맙, 프로카르바진, 알프로스타딜, 질산홀뮴 키토산, 젬시타빈, 독시플루리딘, 페메트렉세드, 테가푸르, 카페시타빈, 기메라신, 오테라실, 아자시티딘, 메토트렉세이트, 우라실, 시타라빈, 플루오로우라실, 플루다가빈, 에노시타빈, 플루타미드, 데시타빈, 카페시타빈, 머캅토푸린, 티오구아닌, 클라드리빈, 카르모퍼, 랄티트렉세드, 도세탁셀, 파클리탁셀, 이리노테칸, 벨로테칸, 토포테칸, 비노렐빈, 에토포시드, 빈크리스틴, 빈블라스틴, 테니포시드, 독소루비신, 이다루비신, 에피루비신, 미톡산트론, 미토마이신, 블레로마이신, 다우노루비신, 닥티노마이신, 피라루비신, 아클라루비신, 페프로마이신, 템시롤리무스, 테모졸로마이드, 부설판, 이포스파미드, 사이클로포스파미드, 멜파란, 알트레트민, 다카바진, 치오테파, 니무스틴, 클로람부실, 미토락톨, 레우코보린, 트레토닌, 엑스메스탄, 아미노글루테시미드, 아나그렐리드, 나벨빈, 파드라졸, 타목시펜, 토레미펜, 테스토락톤, 아나스트로졸, 레트로졸, 보로졸, 비칼루타미드, 로무스틴, 보리노스텟, 엔티노스텟, 5FU, 카르무스틴 및 렌바티닙으로 이루어진 군으로부터 선택되는 어느 하나 이상일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, "cancer treatment drug" refers to a drug for treating cancer, and may be an anticancer drug, and the type is not particularly limited, but may preferably be a drug for the treatment of colorectal cancer. For example, nitrogen mustard, imatinib, oxaliplatin, rituximab, erlotinib, neratinib, lapatinib, gefitinib, vandetanib, nirotinib, semasanib, bosutinib, axitinib, cediranib , restaurtinib, trastuzumab, gefitinib, bortezomib, sunitinib, carboplatin, sorafenib, bevacizumab, cisplatin, cetuximab, viscumalbum, asparaginase, tretinoin, hydroxycarba amide, dasatinib, estramustine, gemtuzumab ozogamicin, ibritumomab tuccetan, heptaplatin, methylaminolevulinic acid, amsacrine, alemtuzumab, procarbazine, alprostadil, holmium nitrate Chitosan, gemcitabine, doxyfluridine, pemetrexed, tegafur, capecitabine, gimeracin, oteracil, azacitidine, methotrexate, uracil, cytarabine, fluorouracil, fludagabine, enocy Tabine, flutamide, decitabine, capecitabine, mercaptopurine, thioguanine, cladribine, carmopher, raltitrexed, docetaxel, paclitaxel, irinotecan, belotecan, topotecan, vinorelbine, etoposide, Vincristine, Vinblastine, Teniposide, Doxorubicin, Idarubicin, Epirubicin, Mitoxantrone, Mitomycin, Bleromycin, Daunorubicin, Dactinomycin, Pyrarubicin, Aclarubicin, Pep Romaycin, temsirolimus, temozolomide, busulfan, ifosfamide, cyclophosphamide, melparan, altretmine, dacarbazine, thiotepa, nimustine, chlorambucil, mitolactol, leucovorin, Tretonin, exemestane, aminoglutethimide, anagrelide, nabelbine, fadrazole, tamoxifen, toremifene, testolactone, anastrozole, letrozole, vorozole, bicalutamide, lomustine, It may be any one or more selected from the group consisting of vorinostat, entinostat, 5FU, carmustine and lenvatinib, but is not limited thereto.
본 발명에서 상기 "내성 극복"이란, 특정 약물에 대한 내성을 획득한 암 세포의 치료용 약물에 대한 감수성을 증가시키는 작용을 의미한다. 본 발명의 목적상 상기 특정 약물은 암 치료용 약물, 특히 항암제를 의미한다. 상기 감수성의 증가는 내성이 없는 암세포에 대해 성장억제 등의 효과를 보이는 농도와 비교하여, 내성을 획득한 암세포의 성장억제 및 세포사멸 등의 효과를 보이는 농도가 동등하거나 그 이상으로 상승시키는 정도에 이르는 것을 의미한다. 상기 내성 극복과 동의어로서 "내성억제", "내성해제", "저항성 해제" 및 "감수성 증강" 등이 있다.In the present invention, the term "overcoming resistance" refers to an action of increasing the sensitivity of cancer cells that have acquired resistance to a specific drug to a drug for treatment. For the purposes of the present invention, the specific drug refers to a drug for treating cancer, particularly an anticancer drug. The increase in sensitivity refers to the extent to which the concentration exhibiting effects such as growth inhibition and apoptosis of cancer cells that have acquired resistance is equal to or higher than the concentration exhibiting effects such as growth inhibition for non-resistant cancer cells. means to reach Synonyms with overcoming the tolerance include "resistance suppression", "resistance release", "resistance release" and "sensitivity enhancement".
본 발명에서, 암의 "재발"은 항암 치료로, 예를 들면 외과적 절제술, 방사선 치료 또는 항암제 치료 후 암을 발견할 수 없다가 일정 기간이 지난 후 다시 발견되는 것을 의미한다. 상기 "재발성 암"은 상기와 같이 암의 재발이 일어난 결과 생긴 암을 의미한다. 특히 대장암의 경우 대장암 치료 후 약 30~50%의 확률로 재발성 대장암이 발생하고, 60% 이상이 처음 상기 대장암 치료 후 2년 내에 발생하며, 나머지 40%가 2년 내지 5년 후에 재발할 수 있다. 상기 대장암이 재발할 경우 절제가 어려운 경우가 많고, 절제가 가능한 경우에도 상당한 규모의 수술을 할 수밖에 없을 수 있다. 또한, 항암 치료 및 방사선 치료에도 제한이 있을 수 있다.In the present invention, "recurrence" of cancer means that cancer cannot be detected after chemotherapy, for example, surgical resection, radiotherapy, or chemotherapy, but is found again after a certain period of time. The “recurrent cancer” refers to a cancer resulting from cancer recurrence as described above. In particular, in the case of colorectal cancer, recurrent colorectal cancer occurs with a probability of about 30-50% after colorectal cancer treatment, and more than 60% occurs within 2 years after the first colorectal cancer treatment, and the remaining 40% occurs within 2 to 5 years. may recur later. When the colorectal cancer recurs, resection is often difficult, and even if resection is possible, a large-scale operation may be inevitable. In addition, there may be limitations in chemotherapy and radiation therapy.
본 발명에서, 상기 "전이"는 암이 원발한 기관이나 부분으로부터 거리상으로 분리되어 있는 다른 곳으로 옮겨가는 성질을 의미한다. 상기 "전이성 암"은 전이하려는 성질을 가진 암 또는 전이가 이루어진 암이다. 특히 상기 전이성 암은 간, 폐, 뼈, 림프절 또는 복강으로 전이되는 것일 수 있으나, 이에 제한되지는 않는다. 상기 전이성 암은 치료가 어렵고, 특히 원발암이 대장암인 전이성 대장암은 간에 전이된 것 중 극히 일부를 제외하고는 수술이 어렵고, 처음 치료과정 보다 진행 양상 및 치료가 복잡할 수 있다.In the present invention, the term "metastasis" refers to the property of cancer to move to another place separated by distance from a primary organ or part. The "metastatic cancer" is a cancer having the property to metastasize or a cancer that has metastasized. In particular, the metastatic cancer may metastasize to the liver, lung, bone, lymph node or abdominal cavity, but is not limited thereto. The metastatic cancer is difficult to treat, and in particular, metastatic colorectal cancer, whose primary cancer is colorectal cancer, is difficult to operate except for a small portion of metastatic colorectal cancer that has metastasized to the liver, and the progression and treatment may be more complicated than the initial treatment process.
본 발명에서 상기 암은 그 발생 부위에 따라 유방암, 담도암, 담낭암, 췌장암, 대장암, 자궁암, 식도암, 위암, 뇌암, 직장암, 폐암, 방광암, 신장암, 난소암, 전립선암, 자궁암, 두경부암, 피부암, 혈액암 및 간암 등 일 수 있고, 바람직하게는 대장암일 수 있으나, 이에 제한되지는 않는다.In the present invention, the cancer is breast cancer, biliary tract cancer, gallbladder cancer, pancreatic cancer, colon cancer, uterine cancer, esophageal cancer, stomach cancer, brain cancer, rectal cancer, lung cancer, bladder cancer, kidney cancer, ovarian cancer, prostate cancer, uterine cancer, head and neck cancer according to the site of occurrence in the present invention , may be skin cancer, blood cancer, liver cancer, etc., preferably colon cancer, but is not limited thereto.
본 발명의 또 다른 구현 예에 따르면, 히스톤 탈아세틸화 저해제(HDAC inhibitor) 및 시스플라틴(Cisplatin)을 유효 성분으로 포함하는 암 줄기세포(Cancer Stem Cell, Tumor Initiating Cells; CSC, TICs)의 성장 억제용 약학적 조성물에 관한 것이다.According to another embodiment of the present invention, for inhibiting the growth of cancer stem cells (Cancer Stem Cell, Tumor Initiating Cells; CSC, TICs) containing a histone deacetylation inhibitor (HDAC inhibitor) and cisplatin as active ingredients It relates to a pharmaceutical composition.
본 발명에서 상기 히스톤 탈아세틸화 저해제로는 상기 화학식 1로 표시되는 N-하이드록시-7-(2-나프틸티오)헵타노마이드(N-hydroxy-7-(2-naphthylthio)heptanomide) 또는 이의 약학적으로 허용되는 염일 수 있다.In the present invention, the histone deacetylation inhibitor is N-hydroxy-7-(2-naphthylthio)heptanomide represented by Formula 1 or its It may be a pharmaceutically acceptable salt.
본 발명에서, 상기 히스톤 탈아세틸화 저해제는 상기 조성물 내에 1μM 내지 20μM 농도로 포함될 수 있다. 상기 HNHA의 농도가 1μM 미만인 경우 조성물의 효과가 충분하게 나타나지 않을 수 있고, 상기 HNHA의 농도가 20μM를 초과하는 경우 정상세포에 대한 조성물의 독성이 커질 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the histone deacetylation inhibitor may be included in the composition at a concentration of 1 μM to 20 μM. When the concentration of HNHA is less than 1 μM, the effect of the composition may not be sufficiently exhibited, and when the concentration of HNHA exceeds 20 μM, toxicity of the composition to normal cells may increase, but is not limited thereto.
본 발명에서, 상기 시스플라틴은 상기 조성물 내에 10μM 내지 200μM의 농도로 포함될 수 있다. 상기 시스플라틴의 농도가 10μM 미만인 경우 조성물의 효과가 충분하게 나타나지 않을 수 있고, 상기 시스플라틴의 농도가 200μM를 초과하는 경우 정상세포에 대한 조성물의 독성이 커질 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the cisplatin may be included in the composition at a concentration of 10 μM to 200 μM. When the concentration of cisplatin is less than 10 μM, the effect of the composition may not be sufficiently exhibited, and when the concentration of cisplatin exceeds 200 μM, toxicity of the composition to normal cells may increase, but is not limited thereto.
또한, 본 발명에서 상기 히스톤 탈아세틸화 저해제와 상기 시스플라틴은 상기 조성물 내에 1:1~100의 몰비로 포함될 수 있고, 상기 히스톤 탈아세틸화 저해제와 상기 시스플라틴의 몰비가 상기한 범위로 포함될 경우 저용량으로 암 치료에 효과적인 시너지 효과를 낼 수 있으나, 이에 제한되는 것은 아니다.In addition, in the present invention, the histone deacetylation inhibitor and the cisplatin may be included in a molar ratio of 1:1 to 100 in the composition, and when the molar ratio of the histone deacetylation inhibitor to the cisplatin is included in the above range, a low dose is used. It may produce an effective synergistic effect in the treatment of cancer, but is not limited thereto.
본 발명에서 상기 암은 유방암, 담도암, 담낭암, 췌장암, 대장암, 자궁암, 식도암, 위암, 뇌암, 직장암, 폐암, 방광암, 신장암, 난소암, 전립선암, 자궁암, 두경부암, 피부암, 혈액암 및 간암으로 이루어진 군으로부터 선택되는 1종 이상의 암일 수 있고, 바람직하게는 대장암일 수 있으며, 종양의 분화 및/또는 증식 등 암의 진행이 본 발명에서 기술하는 암 줄기세포에 의존적인 암의 종류라면 이에 제한되지 않는다.In the present invention, the cancer is breast cancer, biliary tract cancer, gallbladder cancer, pancreatic cancer, colorectal cancer, uterine cancer, esophageal cancer, stomach cancer, brain cancer, rectal cancer, lung cancer, bladder cancer, kidney cancer, ovarian cancer, prostate cancer, uterine cancer, head and neck cancer, skin cancer, blood cancer And it may be one or more cancers selected from the group consisting of liver cancer, preferably colon cancer, and if the cancer progression such as tumor differentiation and/or proliferation is a cancer stem cell-dependent type of cancer described in the present invention It is not limited thereto.
본 발명에서, 상기 암 줄기세포(Cancer Stem CELL, Tumor Initiating Cells; CSC, TICs)는 악성 종양 조직 내에 1 ~ 2% 정도로 존재하며 정상줄기세포의 특성인 자가복제 능력 (self-renewal)과 다른 세포로 분화할 수 있는 전분화능 (pluripotent)을 가지고 있으나 자가 조절 기능에 이상이 있어 세포분열 활성화로 세포 수를 증가하게 되고 스스로 악성 종양 세포로 분화하는 것으로 보고되었다. In the present invention, the cancer stem cells (Cancer Stem CELL, Tumor Initiating Cells; CSC, TICs) are present in about 1 to 2% in the malignant tumor tissue and are different from the self-renewal ability (self-renewal) characteristic of normal stem cells. It has been reported that although it has pluripotent ability to differentiate into malignant tumors, it has an abnormal self-regulatory function.
상기 암 줄기세포는 1997년에 Bonnet 과 Dick이 표면 표지자 CD38를 발현하지 않고 CD34를 발현하는 백혈구 세포 일부 집단을 분리하여 발견하였다(Blood, 1997). 이후, 유방암 (PNAS, 2003), 뇌종양 (Nature, 2004), 전립선암 (Cancer Res, 2005), 대장암 (Nature, 2007), 흑색종 (Nature, 2008)에서도 암 줄기세포가 존재한다는 증거들이 제시되었고. 종양에 포함되어 있는 소수의 암 줄기세포가 종양의 악성화, 항암저항성 및 재발의 주된 원인으로 부각되었다.The cancer stem cells were discovered by Bonnet and Dick in 1997 by isolating a subset of leukocytes expressing CD34 without expressing the surface marker CD38 (Blood, 1997). Since then, evidence has been presented that cancer stem cells are present in breast cancer (PNAS, 2003), brain tumors (Nature, 2004), prostate cancer (Cancer Res, 2005), colorectal cancer (Nature, 2007), and melanoma (Nature, 2008). has become A small number of cancer stem cells contained in tumors has emerged as a major cause of tumor malignancy, anticancer resistance, and recurrence.
암 줄기세포들은 다른 암 세포들과 구별되는 표지 인자(marker)가 존재하며, 암 줄기세포의 표지 인자(cancer stem cell marker)로는 하기 표 1과 같이 다양한 암 종 특이적인 암 줄기세포 표지 인자가 알려져 있다.Cancer stem cells have markers that distinguish them from other cancer cells, and various cancer stem cell markers specific to cancer are known as cancer stem cell markers as shown in Table 1 below. have.
암종carcinoma 암 줄기세포 표지인자Cancer stem cell markers 출처source
교모세포종glioblastoma CD133CD133 　
신장암kidney cancer CD105, CD133CD105, CD133 Contemp Oncol (Pozn). 2015; 19(1A): A44-A51Contemp Oncol (Pozn). 2015; 19(1A): A44-A51
갑상선암thyroid cancer ABCG2, MRP1, LRP 및 CXCR4ABCG2, MRP1, LRP and CXCR4 J Clin Pathol. 2014 Feb;67(2):125-33J Clin Pathol. 2014 Feb;67(2):125-33
급성골수성백혈병 (AMM)Acute myeloid leukemia (AMM) CD34+/CD38-CD34+/CD38- 　
다발성골수종 (multiple myeloma)multiple myeloma CD133-CD133- 　
유방암breast cancer CD44+/CD24-/lowCD44+/CD24-/low Breast Cancer Res. 2007; 9(3): 303Breast Cancer Res. 2007; 9(3): 303
대장암colorectal cancer CD133+CD133+ 　
전립선암prostate cancer CD44+/α2β1hi/CD133+CD44+/α2β1hi/CD133+ 　
흑색종 (melanoma)melanoma ABCB5+ABCB5+ 　
상기한 암 줄기세포들은 끊임없이 자기 재생(self-renewal)을 하며, 실험동물 모델에서 천개 미만의 적은 세포수로도 종양을 만들 수 있으며 악성 종양 세포로서의 능력을 보유하고 있다. 또한 암 치료법인 항암제 치료와 방사선 치료에 놀라울 정도로 저항성을 가지고 있어, 암 줄기세포의 제거는 암 치료의 성패를 가늠할 수 있는 바로미터로 점차 인식되고 있다. 최근에는 수술, 방사선 치료, 항암화학요법 등 기존의 여러 치료 방법을 이용해 암 세포들을 사멸시키더라도 암 줄기세포들을 모두 사멸시키지 못한다면 남아있는 암 줄기세포들로부터 다시 암이 재발할 수 있다는 것으로 인식되고 있다. 이러한 암의 재발을 방지하기 위하여 종양을 재생성할 수 있는 능력을 가진 암 줄기세포를 타겟으로 하는 화학요법 및 이를 바탕으로 암을 치료하고자 하는 치료 프로토콜 개발에 관심이 높아지고 있다.The cancer stem cells described above constantly self-renew, can make tumors with a small number of less than one thousand cells in an experimental animal model, and have the ability as malignant tumor cells. In addition, as they have surprisingly resistance to chemotherapy and radiation therapy, which are cancer treatments, the removal of cancer stem cells is increasingly recognized as a barometer that can measure the success or failure of cancer treatment. Recently, it is recognized that cancer can recur from the remaining cancer stem cells if all cancer stem cells are not killed even if cancer cells are killed using various existing treatment methods such as surgery, radiation therapy, and chemotherapy. . In order to prevent the recurrence of such cancer, interest is growing in chemotherapy targeting cancer stem cells having the ability to regenerate tumors and developing a treatment protocol for treating cancer based on the chemotherapy.
정상 조직에서의 줄기세포는 자가 재생 (self-renewal) 기전에 의해 세포 성장과 분화를 조절하지만, 암 줄기세포는 종양세포 주변의 종양 미세환경 인자에 영향을 받아 비정상적인 자가분열(Self-renewal) 및 유지(maintenance) 경로를 활성화하여 급격히 집적됨으로써 악성화되고, 항암치료에 대한 저항성을 획득하게 되며 궁극적으로 암의 재발을 야기한다고 제시되고 있다. 그러나 아직까지 암 줄기세포의 집적 및 유지를 조절하는 종양 미세 환경 인자의 실체와 상호작용에 대한 구체적인 기전 연구는 진행되지 못하고 있다.Stem cells in normal tissues regulate cell growth and differentiation by a self-renewal mechanism, but cancer stem cells are affected by tumor microenvironmental factors around tumor cells, resulting in abnormal self-renewal and It is suggested that by activating the maintenance pathway and rapidly integrating, it becomes malignant, acquires resistance to chemotherapy, and ultimately causes cancer recurrence. However, a detailed study of the mechanism of interaction with the entity of the tumor microenvironmental factors that control the accumulation and maintenance of cancer stem cells has not yet been conducted.
본 발명에서, 성장 억제의 대상이 되는 암 줄기세포로는 상기 열거된 암의 줄기세포를 모두 포함할 수 있지만, 특히 대장암 줄기세포일 수 있다. In the present invention, the cancer stem cells that are the target of growth inhibition may include all of the above-listed cancer stem cells, but may particularly be colorectal cancer stem cells.
본 발명에서, "암 줄기세포의 성장 억제"란 암 줄기세포 유지(mainternance) 억제, 암 줄기세포 악성화(malignance) 억제 및 암 줄기세포 침윤 활성(invasive) 억제 등의 의미를 포함할 수 있다.In the present invention, "inhibition of growth of cancer stem cells" may include the meaning of inhibiting cancer stem cell maintenance, inhibiting cancer stem cell malignance, and inhibiting cancer stem cell invasive activity.
본 발명에서, "예방"은 본 발명의 약학적 조성물을 이용하여 암 증상을 차단하거나, 암 증상의 억제 또는 지연시키는 모든 행위라면 제한없이 포함할 수 있다. In the present invention, "prevention" may include, without limitation, any action that blocks cancer symptoms or suppresses or delays cancer symptoms using the pharmaceutical composition of the present invention.
본 발명에서, "치료"는 본 발명의 약학적 조성물을 조사하여 암 증상이 호전되거나 이롭게 되는 모든 행위라면 제한없이 포함할 수 있다. In the present invention, "treatment" may include, without limitation, any action in which cancer symptoms are improved or beneficial by examining the pharmaceutical composition of the present invention.
본 발명에 있어서, 상기 약학적 조성물은 캡슐, 정제, 과립, 주사제, 연고제, 분말 또는 음료 형태임을 특징으로 할 수 있으며, 상기 약학적 조성물은 인간을 대상으로 하는 것을 특징으로 할 수 있다. In the present invention, the pharmaceutical composition may be characterized in the form of capsules, tablets, granules, injections, ointments, powders or drinks, and the pharmaceutical composition may be characterized in that it is targeted to humans.
본 발명의 약학적 조성물은 이들로 한정되는 것은 아니지만, 각각 통상의 방법에 따라 산제, 과립제, 캡슐, 정제, 수성 현탁액 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 본 발명의 약학적 조성물은 약제적으로 허용 가능한 담체를 포함할 수 있다. 약제학적으로 허용되는 담체는 경구 투여 시에는 결합제, 활탁제, 붕해제, 부형제, 가용화제, 분산제, 안정화제, 현탁화제, 색소, 향료 등을 사용할 수 있으며, 주사제의 경우에는 완충제, 보존제, 무통화제, 가용화제, 등장제, 안정화제 등을 혼합하여 사용할 수 있으며, 국소투여용의 경우에는 기제, 부형제, 윤활제, 보존제 등을 사용할 수 있다. 본 발명의 약학적 조성물의 제형은 상술한 바와 같은 약제학적으로 허용되는 담체와 혼합하여 다양하게 제조될 수 있다. 예를 들어, 경구 투여시에는 정제, 트로키, 캡슐, 엘릭서(elixir), 서스펜션, 시럽, 웨이퍼 등의 형태로 제조할 수 있으며, 주사제의 경우에는 단위 투약 앰플 또는 다수회 투약 형태로 제조할 수 있다. 기타, 용액, 현탁액, 정제, 캡슐, 서방형 제제 등으로 제형할 수 있다.The pharmaceutical composition of the present invention is not limited thereto, but each can be formulated in the form of oral dosage forms such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories, and sterile injection solutions according to conventional methods. can The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers may include binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, dyes, fragrances, etc. for oral administration, and in the case of injections, buffers, preservatives, pain-freezing agents A topical agent, solubilizer, isotonic agent, stabilizer, etc. can be mixed and used, and in the case of topical administration, a base, excipient, lubricant, preservative, etc. can be used. The dosage form of the pharmaceutical composition of the present invention can be prepared in various ways by mixing with a pharmaceutically acceptable carrier as described above. For example, in the case of oral administration, it can be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and in the case of injections, it can be prepared in the form of unit dose ampoules or multiple doses. have. In addition, it can be formulated as a solution, suspension, tablet, capsule, sustained release formulation, and the like.
한편, 제제화에 적합한 담체, 부형제 및 희석제의 예로는, 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말디톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로즈, 폴리비닐피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 또는 광물유 등이 사용될 수 있다. 또한, 충진제, 항응집제, 윤활제, 습윤제, 향료, 유화제, 방부제 등을 추가로 포함할 수 있다.Meanwhile, examples of suitable carriers, excipients and diluents for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil may be used. In addition, it may further include a filler, an anti-agglomeration agent, a lubricant, a wetting agent, a flavoring agent, an emulsifier, a preservative, and the like.
본 발명에 따른 약학적 조성물의 투여 경로는 이들로 한정되는 것은 아니지만 구강, 정맥내, 근육내, 동맥내, 골수내, 경막내, 심장내, 경피, 피하, 복강내, 비강내, 장관, 국소, 설하 또는 직장이 포함된다. 경구 또는 비경구 투하가 바람직하다. The route of administration of the pharmaceutical composition according to the present invention is not limited thereto, but oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical , sublingual or rectal. Oral or parenteral administration is preferred.
본 발명에서, "비경구"는 피하, 피내, 정맥내, 근육내, 관절내, 활액낭내, 흉골내, 경막내, 병소내 및 두개골내 주사 또는 주입기술을 포함한다. 본 발명의 약학적 조성물은 또한 직장 투여를 위한 좌제의 형태로 투여될 수 있다.In the present invention, "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. The pharmaceutical composition of the present invention may also be administered in the form of a suppository for rectal administration.
본 발명의 약학적 조성물은 사용된 특정 화합물의 활성, 연령, 체중, 일반적인 건강, 성별, 정식, 투여시간, 투여경로, 배출율, 약물 배합 및 예방 또는 치료될 특정 질환의 중증을 포함한 여러 요인에 따라 다양하게 변할 수 있고, 상기 약학적 조성물의 투여량은 환자의 상태, 체중, 질병의 정도, 약무형태, 투여경로 및 기간에 따라 다르지만 당업자에 의해 적절하게 선택될 수 있고, 1일 0.0001 내지 50mg/kg 또는 0.001 내지 50mg/kg으로 투여할 수 있다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다. 본 발명에 따른 의약 조성물은 환제, 당의정, 캡슐, 액제, 겔, 시럽, 슬러리, 현탁제로 제형될 수 있다.The pharmaceutical composition of the present invention depends on several factors including the activity of the specific compound used, age, weight, general health, sex, formula, administration time, administration route, excretion rate, drug formulation, and the severity of the specific disease to be prevented or treated. The dosage of the pharmaceutical composition may vary depending on the patient's condition, weight, disease severity, drug form, administration route and period, but may be appropriately selected by those skilled in the art, and 0.0001 to 50 mg/day kg or 0.001 to 50 mg/kg. Administration may be administered once a day, or may be administered in several divided doses. The above dosage does not limit the scope of the present invention in any way. The pharmaceutical composition according to the present invention may be formulated as pills, dragees, capsules, solutions, gels, syrups, slurries, and suspensions.
본 발명의 또 다른 구현 예에 따르면, 투여가 필요한 개체에게 히스톤 탈아세틸화 저해제(HDAC inhibitor) 및 시스플라틴(Cisplatin)을 유효량으로 투여하는 단계를 포함하는, 암의 예방 또는 치료 방법에 관한 것이다. According to another embodiment of the present invention, it relates to a method for preventing or treating cancer, comprising administering an effective amount of a histone deacetylation inhibitor (HDAC inhibitor) and cisplatin to an individual in need of administration.
본 발명에서 상기 히스톤 탈아세틸화 저해제로는 상기 화학식 1로 표시되는 N-하이드록시-7-(2-나프틸티오)헵타노마이드(N-hydroxy-7-(2-naphthylthio)heptanomide) 또는 이의 약학적으로 허용되는 염일 수 있다.In the present invention, the histone deacetylation inhibitor is N-hydroxy-7-(2-naphthylthio)heptanomide represented by Formula 1 or its It may be a pharmaceutically acceptable salt.
본 발명에서, 상기 히스톤 탈아세틸화 저해제는 1μM 내지 20μM 농도로 투여될 수 있고, 상기 히스톤 탈아세틸화 저해제의 농도가 1μM 미만인 경우 조성물의 효과가 충분하게 나타나지 않을 수 있고, 상기 히스톤 탈아세틸화 저해제의 농도가 20μM를 초과하는 경우 정상세포에 대한 독성이 커질 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the histone deacetylation inhibitor may be administered at a concentration of 1 μM to 20 μM, and when the concentration of the histone deacetylation inhibitor is less than 1 μM, the effect of the composition may not be sufficiently exhibited, and the histone deacetylation inhibitor If the concentration of is more than 20 μM, the toxicity to normal cells may increase, but is not limited thereto.
본 발명에서, 상기 시스플라틴은 10μM 내지 200μM의 농도로 투여될 수 있고, 상기 시스플라틴의 농도가 10μM 미만인 경우 조성물의 효과가 충분하게 나타나지 않을 수 있고, 상기 시스플라틴의 농도가 200μM를 초과하는 경우 정상세포에 대한 조성물의 독성이 커질 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the cisplatin may be administered at a concentration of 10 μM to 200 μM, and when the concentration of cisplatin is less than 10 μM, the effect of the composition may not be sufficiently exhibited. The toxicity of the composition may increase, but is not limited thereto.
또한, 본 발명에서 상기 히스톤 탈아세틸화 저해제와 상기 시스플라틴은 1:1~100의 몰비로 투여될 수 있고, 상기 히스톤 탈아세틸화 저해제와 상기 시스플라틴의 몰비가 상기한 범위로 포함될 경우 저용량으로 암 치료에 효과적인 시너지 효과를 낼 수 있으나, 이에 제한되는 것은 아니다.In addition, in the present invention, the histone deacetylation inhibitor and the cisplatin may be administered in a molar ratio of 1:1 to 100, and when the molar ratio of the histone deacetylation inhibitor and the cisplatin is included in the above range, cancer treatment with a low dose can produce an effective synergistic effect, but is not limited thereto.
본 발명에서 상기 히스톤 탈아세틸화 저해제와 상기 시스플라틴은 동시, 개별 또는 순차 투여될 수 있고, 두 약물의 투여 순서는 특별히 제한하지 않는다. In the present invention, the histone deacetylation inhibitor and the cisplatin may be administered simultaneously, separately, or sequentially, and the order of administration of the two drugs is not particularly limited.
본 발명에서 상기 암은 그 발생 부위에 따라 유방암, 담도암, 담낭암, 췌장암, 대장암, 자궁암, 식도암, 위암, 뇌암, 직장암, 폐암, 방광암, 신장암, 난소암, 전립선암, 자궁암, 두경부암, 피부암, 혈액암 및 간암 등 일 수 있고, 바람직하게는 대장암일 수 있으나, 이에 제한되지는 않는다.In the present invention, the cancer is breast cancer, biliary tract cancer, gallbladder cancer, pancreatic cancer, colon cancer, uterine cancer, esophageal cancer, stomach cancer, brain cancer, rectal cancer, lung cancer, bladder cancer, kidney cancer, ovarian cancer, prostate cancer, uterine cancer, head and neck cancer according to the site of occurrence in the present invention , may be skin cancer, blood cancer, liver cancer, etc., preferably colon cancer, but is not limited thereto.
본 발명의 또 다른 구현 예에 따르면, 투여가 필요한 개체에게 히스톤 탈아세틸화 저해제(HDAC inhibitor) 및 시스플라틴(Cisplatin)을 유효량으로 투여하는 단계를 포함하는, 내성 암, 재발성 암 또는 전이성 암의 예방 또는 치료 방법에 관한 것이다. According to another embodiment of the present invention, prevention of resistant cancer, recurrent cancer or metastatic cancer, comprising administering an effective amount of a histone deacetylation inhibitor (HDAC inhibitor) and cisplatin to an individual in need of administration or to a method of treatment.
본 발명에서 상기 히스톤 탈아세틸화 저해제로는 상기 화학식 1로 표시되는 N-하이드록시-7-(2-나프틸티오)헵타노마이드(N-hydroxy-7-(2-naphthylthio)heptanomide) 또는 이의 약학적으로 허용되는 염일 수 있다.In the present invention, the histone deacetylation inhibitor is N-hydroxy-7-(2-naphthylthio)heptanomide represented by Formula 1 or its It may be a pharmaceutically acceptable salt.
본 발명에서, 상기 히스톤 탈아세틸화 저해제는 1μM 내지 20μM 농도로 투여될 수 있고, 상기 히스톤 탈아세틸화 저해제의 농도가 1μM 미만인 경우 조성물의 효과가 충분하게 나타나지 않을 수 있고, 상기 히스톤 탈아세틸화 저해제의 농도가 20μM를 초과하는 경우 정상세포에 대한 독성이 커질 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the histone deacetylation inhibitor may be administered at a concentration of 1 μM to 20 μM, and when the concentration of the histone deacetylation inhibitor is less than 1 μM, the effect of the composition may not be sufficiently exhibited, and the histone deacetylation inhibitor If the concentration of is more than 20 μM, the toxicity to normal cells may increase, but is not limited thereto.
본 발명에서, 상기 시스플라틴은 10μM 내지 200μM의 농도로 투여될 수 있고, 상기 시스플라틴의 농도가 10μM 미만인 경우 조성물의 효과가 충분하게 나타나지 않을 수 있고, 상기 시스플라틴의 농도가 200μM를 초과하는 경우 정상세포에 대한 조성물의 독성이 커질 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the cisplatin may be administered at a concentration of 10 μM to 200 μM, and when the concentration of cisplatin is less than 10 μM, the effect of the composition may not be sufficiently exhibited. The toxicity of the composition may increase, but is not limited thereto.
또한, 본 발명에서 상기 히스톤 탈아세틸화 저해제와 상기 시스플라틴은 1:1~100의 몰비로 투여될 수 있고, 상기 히스톤 탈아세틸화 저해제와 상기 시스플라틴의 몰비가 상기한 범위로 포함될 경우 저용량으로 암 치료에 효과적인 시너지 효과를 낼 수 있으나, 이에 제한되는 것은 아니다.In addition, in the present invention, the histone deacetylation inhibitor and the cisplatin may be administered in a molar ratio of 1:1 to 100, and when the molar ratio of the histone deacetylation inhibitor and the cisplatin is included in the above range, cancer treatment with a low dose can produce an effective synergistic effect, but is not limited thereto.
본 발명에서 상기 히스톤 탈아세틸화 저해제와 상기 시스플라틴은 동시, 개별 또는 순차 투여될 수 있고, 두 약물의 투여 순서는 특별히 제한하지 않는다. In the present invention, the histone deacetylation inhibitor and the cisplatin may be administered simultaneously, separately, or sequentially, and the order of administration of the two drugs is not particularly limited.
본 발명에서 상기 내성 암은 암 치료용 약물, 특히 항암제 치료에 대하여 내성을 갖는 암으로, 상기 항암제의 종류를 특별히 제한하지는 않으나, 바람직하게는 대장암의 치료용 약물일 수 있다. 구체적인 예를 들면, 나이트로젠 머스타드, 이마티닙, 옥살리플라틴, 리툭시맙, 엘로티닙, 네라티닙, 라파티닙, 제피티닙, 반데타닙, 니로티닙, 세마사닙, 보수티닙, 악시티닙, 세디라닙, 레스타우르티닙, 트라스투주맙, 게피티니브, 보르테조밉, 수니티닙, 카보플라틴, 소라페닙, 베바시주맙, 시스플라틴, 세툭시맙, 비스쿰알붐, 아스파라기나제, 트레티노인, 하이드록시카바마이드, 다사티닙, 에스트라머스틴, 겜투주맵오조가마이신, 이브리투모맙튜세탄, 헵타플라틴, 메칠아미노레불린산, 암사크린, 알렘투주맙, 프로카르바진, 알프로스타딜, 질산홀뮴 키토산, 젬시타빈, 독시플루리딘, 페메트렉세드, 테가푸르, 카페시타빈, 기메라신, 오테라실, 아자시티딘, 메토트렉세이트, 우라실, 시타라빈, 플루오로우라실, 플루다가빈, 에노시타빈, 플루타미드, 데시타빈, 카페시타빈, 머캅토푸린, 티오구아닌, 클라드리빈, 카르모퍼, 랄티트렉세드, 도세탁셀, 파클리탁셀, 이리노테칸, 벨로테칸, 토포테칸, 비노렐빈, 에토포시드, 빈크리스틴, 빈블라스틴, 테니포시드, 독소루비신, 이다루비신, 에피루비신, 미톡산트론, 미토마이신, 블레로마이신, 다우노루비신, 닥티노마이신, 피라루비신, 아클라루비신, 페프로마이신, 템시롤리무스, 테모졸로마이드, 부설판, 이포스파미드, 사이클로포스파미드, 멜파란, 알트레트민, 다카바진, 치오테파, 니무스틴, 클로람부실, 미토락톨, 레우코보린, 트레토닌, 엑스메스탄, 아미노글루테시미드, 아나그렐리드, 나벨빈, 파드라졸, 타목시펜, 토레미펜, 테스토락톤, 아나스트로졸, 레트로졸, 보로졸, 비칼루타미드, 로무스틴, 보리노스텟, 엔티노스텟, 5FU, 카르무스틴 및 렌바티닙으로 이루어진 군으로부터 선택되는 어느 하나 이상일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the resistant cancer is a cancer having resistance to a drug for cancer treatment, particularly an anticancer drug, and the type of the anticancer agent is not particularly limited, but may preferably be a drug for the treatment of colorectal cancer. Specific examples include nitrogen mustard, imatinib, oxaliplatin, rituximab, erlotinib, neratinib, lapatinib, gefitinib, vandetanib, nirotinib, semasanib, bosutinib, axitinib, cediranib , restaurtinib, trastuzumab, gefitinib, bortezomib, sunitinib, carboplatin, sorafenib, bevacizumab, cisplatin, cetuximab, viscumalbum, asparaginase, tretinoin, hydroxycarba amide, dasatinib, estramustine, gemtuzumab ozogamicin, ibritumomab tuccetan, heptaplatin, methylaminolevulinic acid, amsacrine, alemtuzumab, procarbazine, alprostadil, holmium nitrate Chitosan, gemcitabine, doxyfluridine, pemetrexed, tegafur, capecitabine, gimeracin, oteracil, azacitidine, methotrexate, uracil, cytarabine, fluorouracil, fludagabine, enocy Tabine, flutamide, decitabine, capecitabine, mercaptopurine, thioguanine, cladribine, carmopher, raltitrexed, docetaxel, paclitaxel, irinotecan, belotecan, topotecan, vinorelbine, etoposide, Vincristine, vinblastine, teniposide, doxorubicin, idarubicin, epirubicin, mitoxantrone, mitomycin, bleromycin, daunorubicin, dactinomycin, pyrarubicin, aclarubicin, pep Romaycin, temsirolimus, temozolomide, busulfan, ifosfamide, cyclophosphamide, melparan, altretmine, dacarbazine, thiotepa, nimustine, chlorambucil, mitolactol, leucovorin, Tretonin, exemestane, aminoglutethimide, anagrelide, nabelbine, fadrazole, tamoxifen, toremifene, testolactone, anastrozole, letrozole, vorozole, bicalutamide, lomustine, It may be any one or more selected from the group consisting of vorinostat, entinostat, 5FU, carmustine and lenvatinib, but is not limited thereto.
본 발명에서 상기 암은 그 발생 부위에 따라 유방암, 담도암, 담낭암, 췌장암, 대장암, 자궁암, 식도암, 위암, 뇌암, 직장암, 폐암, 방광암, 신장암, 난소암, 전립선암, 자궁암, 두경부암, 피부암, 혈액암 및 간암 등 일 수 있고, 바람직하게는 대장암일 수 있으나, 이에 제한되지는 않는다.In the present invention, the cancer is breast cancer, biliary tract cancer, gallbladder cancer, pancreatic cancer, colon cancer, uterine cancer, esophageal cancer, stomach cancer, brain cancer, rectal cancer, lung cancer, bladder cancer, kidney cancer, ovarian cancer, prostate cancer, uterine cancer, head and neck cancer according to the site of occurrence in the present invention , may be skin cancer, blood cancer, liver cancer, etc., preferably colon cancer, but is not limited thereto.
본 발명의 또 다른 구현 예에 따르면, 투여가 필요한 개체에게 히스톤 탈아세틸화 저해제(HDAC inhibitor) 및 시스플라틴(Cisplatin)을 유효량으로 투여하는 단계를 포함하는, 암 줄기세포(CSC, TICs)의 성장 억제 방법에 관한 것이다. According to another embodiment of the present invention, growth inhibition of cancer stem cells (CSCs, TICs), comprising administering an effective amount of a histone deacetylation inhibitor (HDAC inhibitor) and cisplatin to an individual in need of administration it's about how
본 발명에서 상기 히스톤 탈아세틸화 저해제로는 상기 화학식 1로 표시되는 N-하이드록시-7-(2-나프틸티오)헵타노마이드(N-hydroxy-7-(2-naphthylthio)heptanomide) 또는 이의 약학적으로 허용되는 염일 수 있다.In the present invention, the histone deacetylation inhibitor is N-hydroxy-7-(2-naphthylthio)heptanomide represented by Formula 1 or its It may be a pharmaceutically acceptable salt.
본 발명에서, 상기 히스톤 탈아세틸화 저해제는 1μM 내지 20μM 농도로 투여될 수 있고, 상기 히스톤 탈아세틸화 저해제의 농도가 1μM 미만인 경우 조성물의 효과가 충분하게 나타나지 않을 수 있고, 상기 히스톤 탈아세틸화 저해제의 농도가 20μM를 초과하는 경우 정상세포에 대한 독성이 커질 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the histone deacetylation inhibitor may be administered at a concentration of 1 μM to 20 μM, and when the concentration of the histone deacetylation inhibitor is less than 1 μM, the effect of the composition may not be sufficiently exhibited, and the histone deacetylation inhibitor If the concentration of is more than 20 μM, the toxicity to normal cells may increase, but is not limited thereto.
본 발명에서, 상기 시스플라틴은 10μM 내지 200μM의 농도로 투여될 수 있고, 상기 시스플라틴의 농도가 10μM 미만인 경우 조성물의 효과가 충분하게 나타나지 않을 수 있고, 상기 시스플라틴의 농도가 200μM를 초과하는 경우 정상세포에 대한 조성물의 독성이 커질 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the cisplatin may be administered at a concentration of 10 μM to 200 μM, and when the concentration of cisplatin is less than 10 μM, the effect of the composition may not be sufficiently exhibited. The toxicity of the composition may increase, but is not limited thereto.
또한, 본 발명에서 상기 히스톤 탈아세틸화 저해제와 상기 시스플라틴은 1:1~100의 몰비로 투여될 수 있고, 상기 히스톤 탈아세틸화 저해제와 상기 시스플라틴의 몰비가 상기한 범위로 포함될 경우 저용량으로 암 치료에 효과적인 시너지 효과를 낼 수 있으나, 이에 제한되는 것은 아니다.In addition, in the present invention, the histone deacetylation inhibitor and the cisplatin may be administered in a molar ratio of 1:1 to 100, and when the molar ratio of the histone deacetylation inhibitor and the cisplatin is included in the above range, cancer treatment with a low dose can produce an effective synergistic effect, but is not limited thereto.
본 발명에서 상기 히스톤 탈아세틸화 저해제와 상기 시스플라틴은 동시, 개별 또는 순차 투여될 수 있고, 두 약물의 투여 순서는 특별히 제한하지 않는다. In the present invention, the histone deacetylation inhibitor and the cisplatin may be administered simultaneously, separately, or sequentially, and the order of administration of the two drugs is not particularly limited.
본 발명에서 상기 암은 그 발생 부위에 따라 유방암, 담도암, 담낭암, 췌장암, 대장암, 자궁암, 식도암, 위암, 뇌암, 직장암, 폐암, 방광암, 신장암, 난소암, 전립선암, 자궁암, 두경부암, 피부암, 혈액암 및 간암 등 일 수 있고, 바람직하게는 대장암일 수 있으나, 이에 제한되지는 않는다.In the present invention, the cancer is breast cancer, biliary tract cancer, gallbladder cancer, pancreatic cancer, colon cancer, uterine cancer, esophageal cancer, stomach cancer, brain cancer, rectal cancer, lung cancer, bladder cancer, kidney cancer, ovarian cancer, prostate cancer, uterine cancer, head and neck cancer according to the site of occurrence in the present invention , may be skin cancer, blood cancer, liver cancer, etc., preferably colon cancer, but is not limited thereto.
본 발명의 각 방법에서, 상기 히스톤 탈아세틸화 저해제 및 시스플라틴의 투여량, 스케줄 및 투여 경로는 개체의 크기 및 조건에 따라, 그리고 표준 약제학적 관행에 따라 결정될 수 있다. 예시적인 투여 경로는 정맥내, 동맥내, 복강내, 폐내, 혈관내, 근육내, 기관내, 피하, 안내, 척수강내 또는 경피를 포함한다. In each method of the present invention, the dose, schedule, and route of administration of the histone deacetylation inhibitor and cisplatin may be determined according to the size and condition of the individual and according to standard pharmaceutical practice. Exemplary routes of administration include intravenous, intraarterial, intraperitoneal, intrapulmonary, intravascular, intramuscular, intratracheal, subcutaneous, intraocular, intrathecal, or transdermal.
개체에 투여되는 용량은, 예를 들어, 투여되는 유효 성분의 특정 유형, 투여 경로 및 치료되는 질환의 특정 유형과 병기에 따라 달라질 수 있다. 상기 양은 심한 독성 또는 유해 사례없이, 질환에 대한 치료 반응과 같은 원하는 반응을 가져오기 충분해야 한다. 일부 실시 형태에서, 유효 성분의 양은 치료 전의 동일한 개체에서의 상응하는 질환과 비교하여, 또는 치료를 받지 않은 다른 개체에서의 상응하는 활성과 비교하여 적어도 약 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% 또는 100% 중 어느 하나만큼 질환의 진행을 감소시키거나, 질환을 개선시키거나 질환을 치료시키기 충분한 양이다. 정제된 효소를 사용한 시험관내 검정, 세포 기반 검정, 동물 모델 또는 인체 실험과 같은 표준 방법을 사용하여 효과의 규모를 측정할 수 있다.The dose administered to a subject may vary depending, for example, on the particular type of active ingredient administered, the route of administration, and the particular type and stage of the disease being treated. The amount should be sufficient to produce a desired response, such as a therapeutic response to the disease, without severe toxicity or adverse events. In some embodiments, the amount of active ingredient is at least about 10%, 20%, 30%, 40% compared to the corresponding disease in the same subject prior to treatment, or compared to the corresponding activity in another subject not receiving treatment. , 50%, 60%, 70%, 80%, 90%, 95% or 100% in an amount sufficient to reduce the progression of the disease, ameliorate the disease, or treat the disease. Standard methods such as in vitro assays with purified enzymes, cell-based assays, animal models or human experiments can be used to measure the magnitude of the effect.
본 발명에 따른 약학적 조성물은 히스톤 탈아세틸화 저해제와 시스플라틴을 함께 사용하여 암 세포 또는 암 줄기세포의 증식을 효과적으로 억제하여, 암을 예방 또는 치료할 수 있으며, 더 나아가 약제의 내성이 생기는 것을 방지하거나 혹은 기 생성된 내성을 극복하여 항암제에 대한 감수성을 증진시킬 수 있고, 그 외에도 암의 재발이나 원발암에서 타 기관이나 조직으로의 암이 전이하는 것을 예방하거나, 재발된 암 또는 전이된 암을 효과적으로 치료할 수 있다. The pharmaceutical composition according to the present invention can prevent or treat cancer by effectively inhibiting the proliferation of cancer cells or cancer stem cells by using a histone deacetylation inhibitor and cisplatin together, and further preventing or preventing drug resistance from occurring Alternatively, it is possible to increase the sensitivity to anticancer drugs by overcoming the previously generated resistance, and, in addition, prevent cancer recurrence or metastasis of cancer from the primary cancer to other organs or tissues, or effectively treat relapsed or metastasized cancer can be treated
도 1은 본 발명의 일 실시예에 따른 HT-29 대장암 세포주에 시스플라틴 및 HNHA를 단독 또는 이들 혼합물을 처리한 경우 세포수를 그래프로 나타낸 것이다.1 is a graph showing the number of cells when cisplatin and HNHA alone or a mixture thereof is treated in HT-29 colorectal cancer cell line according to an embodiment of the present invention.
도 2는 본 발명의 일 실시예에 따른 재발성 대장암 세포주에 시스플라틴 및 HNHA를 단독 또는 이들 혼합물을 처리한 경우 세포수를 그래프로 나타낸 것이다.2 is a graph showing the number of cells in the case of treatment with cisplatin and HNHA alone or a mixture thereof in the recurrent colorectal cancer cell line according to an embodiment of the present invention.
도 3은 본 발명의 일 실시예에 따른 전이성 대장암 세포주에 시스플라틴 및 HNHA를 단독 또는 이들 혼합물을 처리한 경우 세포수를 그래프로 나타낸 것이다.3 is a graph showing the number of cells when treated with cisplatin and HNHA alone or a mixture thereof in a metastatic colorectal cancer cell line according to an embodiment of the present invention.
본 발명의 일 구현 예에 따르면, 히스톤 탈아세틸화 저해제(Histone Deacetylation inhibitor; HDAC inhibitor)로 바람직하게는 N-하이드록시-7-(2-나프틸티오)헵타노마이드(N-hydroxy-7-(2-naphthylthio)heptanomide) 또는 이의 약학적으로 허용되는 염; 및 시스플라틴(Cisplatin)을 유효 성분으로 포함하는 암의 예방 또는 치료용 약학적 조성물에 관한 것이다. According to one embodiment of the present invention, preferably as a histone deacetylation inhibitor (HDAC inhibitor), N-hydroxy-7-(2-naphthylthio)heptanomide (N-hydroxy-7- (2-naphthylthio)heptanomide) or a pharmaceutically acceptable salt thereof; And it relates to a pharmaceutical composition for preventing or treating cancer comprising cisplatin as an active ingredient.
본 발명의 다른 구현 예에 따르면, 히스톤 탈아세틸화 저해제(HDAC inhibitor)로 바람직하게는 N-하이드록시-7-(2-나프틸티오)헵타노마이드(N-hydroxy-7-(2-naphthylthio)heptanomide) 또는 이의 약학적으로 허용되는 염; 및 시스플라틴(Cisplatin)을 유효 성분으로 포함하는 내성 암, 재발성 암 또는 전이성 암의 예방 또는 치료용 약학적 조성물에 관한 것이다.According to another embodiment of the present invention, as a histone deacetylation inhibitor (HDAC inhibitor), preferably N-hydroxy-7-(2-naphthylthio)heptanomide (N-hydroxy-7-(2-naphthylthio) ) heptanomide) or a pharmaceutically acceptable salt thereof; And it relates to a pharmaceutical composition for preventing or treating resistant cancer, recurrent cancer, or metastatic cancer comprising cisplatin as an active ingredient.
본 발명의 다른 구현 예에 따르면, 히스톤 탈아세틸화 저해제(HDAC inhibitor)로 바람직하게는 N-하이드록시-7-(2-나프틸티오)헵타노마이드(N-hydroxy-7-(2-naphthylthio)heptanomide) 또는 이의 약학적으로 허용되는 염; 및 시스플라틴(Cisplatin)을 유효 성분으로 포함하는 암 줄기세포(Cancer Stem Cell, Tumor Initiating Cells; CSC, TICs)의 성장 억제용 약학적 조성물에 관한 것이다.According to another embodiment of the present invention, as a histone deacetylation inhibitor (HDAC inhibitor), preferably N-hydroxy-7-(2-naphthylthio)heptanomide (N-hydroxy-7-(2-naphthylthio) ) heptanomide) or a pharmaceutically acceptable salt thereof; And it relates to a pharmaceutical composition for inhibiting the growth of cancer stem cells (Cancer Stem Cell, Tumor Initiating Cells; CSC, TICs) comprising cisplatin as an active ingredient.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로서, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .
실시예Example
환자/조직 샘플로부터 종양 세포 분리 및 1차 배양Isolation and primary culture of tumor cells from patient/tissue samples
연세대학교 강남 세브란스 병원의 하기 표 2의 대장암 환자로부터 종양 덩어리를 확보한 뒤 하기의 과정을 거쳐 대장암 세포주인 YUMC-C1, YUMC-C2 세포를 얻었다. After obtaining a tumor mass from a colorectal cancer patient shown in Table 2 below at Yonsei University Gangnam Severance Hospital, YUMC-C1 and YUMC-C2 cells, which are colon cancer cell lines, were obtained through the following procedure.
구체적으로, 상기 종양 덩어리는 대장암의 원발 부위 및 전이 부위의 외과적 절제술 중에 확보하였다. 절제술 다음날에 획득한 종양 덩어리를 항진균제 및 항생제를 포함하는 생리 식염수에 보관한 뒤 실험실로 이동하였다. 상기 종양 덩어리로부터 정상 조직과 지방을 제거한 뒤, 종양 조직을 1X HBSS로 세척하였다. 종양 조직을 튜브 내에서 해리 배지와 함께 분쇄하였다. 해리 배지는 콜라게나제 Ⅳ형(Sigma, USA) 1mg/ml 및 20% FBS를 포함하는 DMEM/F12를 사용하였다. 분쇄되어 부유하는 종양 세포를 50ml 1X HBSS로 세척하며 멸균 70-마이크로 포어 나일론 세포 스트레이너(BD Falcom)로 여과한 후 1400 rpm으로 5분 동안 원심 분리하였다. 세포를 10% 소태아 혈청(Hyclone, South Logan, UT, USA) 및 2% 페니실린/스트렙토마이신 용액(Gibco, Grand Island, NY, USA)를 포함하는 RPMI-1640(Hyclone) 배지에 재부유시켰다. 세포 생존율은 트립판 블루 염색 배제법에 의하여 측정하였다. Specifically, the tumor mass was obtained during surgical resection of the primary site and metastasis site of colorectal cancer. The tumor mass obtained the day after resection was stored in physiological saline containing antifungal and antibiotics, and then moved to the laboratory. After removing normal tissue and fat from the tumor mass, the tumor tissue was washed with 1X HBSS. Tumor tissue was triturated with dissociation medium in tubes. As the dissociation medium, DMEM/F12 containing 1 mg/ml of collagenase type IV (Sigma, USA) and 20% FBS was used. The crushed and suspended tumor cells were washed with 50ml 1X HBSS, filtered with a sterile 70-micropore nylon cell strainer (BD Falcom), and centrifuged at 1400 rpm for 5 minutes. Cells were resuspended in RPMI-1640 (Hyclone) medium containing 10% fetal bovine serum (Hyclone, South Logan, UT, USA) and 2% penicillin/streptomycin solution (Gibco, Grand Island, NY, USA). Cell viability was measured by trypan blue staining exclusion method.
구분division HT-29HT-29 YUMC-C1YUMC-C1 YUMC-C2YUMC-C2
진단 시 나이age at diagnosis -- 7171 6363
성별gender -- 여성woman 남성male
1차 병변primary lesion 대장암colorectal cancer 대장암colorectal cancer 대장암colorectal cancer
2차 병변secondary lesion -- 방사선 치료 후 원발 부위에서 재발Recurrence at the primary site after radiation therapy 간 전이liver metastases
암 기(stage)cancer stage -- IVcIVc IVcIVc
배양 시 사용한 샘플의 분류Classification of samples used in culture -- 새로운 종양new tumor 새로운 종양new tumor
종양 덩어리 확보처Tumor mass acquisition site ATCCATCC 대한민국 서울 강남 세브란스 병원Severance Hospital, Gangnam, Seoul, South Korea 대한민국 서울 강남 세브란스 병원Severance Hospital, Gangnam, Seoul, South Korea
세포 배양cell culture
상기와 같이 (1) 대조군으로 사용된 대장암 세포주 HT-29, (2) 환자로부터 유래된 재발성 대장암 세포주인 YUMC-C1, (3) 환자로부터 유래된 전이성 대장암 세포주인 YUMC-C2 세포를 각각 분리한 뒤, 10% 소태아 혈청을 포함하는 RPMI-1640 배지에서 배양하였다. As described above, (1) the colorectal cancer cell line HT-29 used as a control, (2) YUMC-C1, a recurrent colorectal cancer cell line derived from a patient, and (3) YUMC-C2 cells, a metastatic colorectal cancer cell line derived from a patient After each separation, cultured in RPMI-1640 medium containing 10% fetal bovine serum.
HNHA 및 시스플라틴 병용 조합의 대장암 세포주에 대한 IC50 측정IC50 determination of HNHA and Cisplatin Combination Combination for Colorectal Cancer Cell Lines
(1) 대조군으로 사용된 대장암 세포주 HT-29, (2) 환자로부터 유래된 재발성 대장암 세포주인 YUMC-C1, (3) 환자로부터 유래된 전이성 대장암 세포주인 YUMC-C2 세포에 시스플라틴 및 HNHA를 병용 투여하는 경우 항암 효과에 시너지 효과가 부여되는지 확인하기 위하여, HT-29, YUMC-C1, YUMC-C2 세포 각각에 HNHA, 시스플라틴 각각 또는 이들을 병용으로 처리한 후 MTT 어쎄이에 의하여 IC50을 측정하여 그 결과를 하기 표 3에 나타내었다. (1) colorectal cancer cell line HT-29 used as a control, (2) YUMC-C1, a recurrent colorectal cancer cell line derived from a patient, (3) cisplatin and YUMC-C2 cells, a metastatic colorectal cancer cell line derived from a patient In order to determine whether a synergistic effect is imparted to the anticancer effect when HNHA is administered in combination, each of HT-29, YUMC-C1, and YUMC-C2 cells was treated with HNHA, cisplatin, or these in combination, and then IC 50 was measured by MTT assay. were measured and the results are shown in Table 3 below.
세포주cell line 조직 병리학histopathology 동물animal 세포 증식 IC50(μM)Cell proliferation IC 50 (μM)
시스플라틴cisplatin HNHAHNHA 시스플라틴 + HNHACisplatin + HNHA
HT-29HT-29 대장암colorectal cancer 인간human 70.1(±0.2)70.1 (±0.2) 19.5(±0.1)19.5 (±0.1) 20.1(±0.5) + 4.2(±0.1)20.1 (±0.5) + 4.2 (±0.1)
YUMC-C1YUMC-C1 대장암colorectal cancer 인간human 241.2(±0.1)241.2 (±0.1) 40.4(±0.5)40.4 (±0.5) 104.3(±0.2) + 10.4(±0.3)104.3 (±0.2) + 10.4 (±0.3)
YUMC-C2YUMC-C2 대장암colorectal cancer 인간human 247.1(±0.3)247.1 (±0.3) 45.4(±0.2)45.4 (±0.2) 113.4(±0.1) + 13.2(±0.2)113.4 (±0.1) + 13.2 (±0.2)
상기 표 3에서 보는 바와 같이, (1) 대조군으로 사용된 대장암 세포주 HT-29, (2) 환자로부터 유래된 재발성 대장암 세포주인 YUMC-C1, (3) 환자로부터 유래된 전이성 대장암 세포주인 YUMC-C2 세포 모두에서 시스플라틴과 HNHA을 병용 투여한 경우 시스플라틴을 단독으로 투여한 경우나, HNHA을 단독으로 투여한 경우보다 IC50이 현저히 낮은 값을 보였다.As shown in Table 3 above, (1) colorectal cancer cell line HT-29 used as a control, (2) YUMC-C1, a recurrent colorectal cancer cell line derived from a patient, (3) metastatic colorectal cancer cell line derived from a patient In both YUMC-C2 cells, when cisplatin and HNHA were administered in combination, IC 50 was significantly lower than when cisplatin was administered alone or when HNHA was administered alone.
HNHA 및 시스플라틴의 병용 조합에 의한 암 세포 증식 억제의 시너지 효과 분석Analysis of Synergistic Effects of Cancer Cell Proliferation Inhibition by Combination of HNHA and Cisplatin
(1) 대조군으로 사용된 대장암 세포주 HT-29, (2) 환자로부터 유래된 재발성 대장암 세포주인 YUMC-C1, (3) 환자로부터 유래된 전이성 대장암 세포주인 YUMC-C2 세포에 시스플라틴 및 HNHA를 병용 투여하는 경우 항암 효과에 시너지 효과가 부여되는지 확인하기 위하여, HT-29, YUMC-C1, YUMC-C2 세포 각각에 HNHA; 시스플라틴; 렌바티닙; 시스플라틴 및 HNHA를 병용 투여(Cisplatin+HNHA; C+H); 렌바티닙 및 HNHA를 병용 투여(Lenvatinib+HNHA; L+H)한 후 MTT 어쎄이에 의하여 시간에 따른 암 세포의 수를 분석하여, 그 결과를 도 1 내지 3에 나타내었다. (1) colorectal cancer cell line HT-29 used as a control, (2) YUMC-C1, a recurrent colorectal cancer cell line derived from a patient, (3) cisplatin and YUMC-C2 cells, a metastatic colorectal cancer cell line derived from a patient In order to determine whether a synergistic effect is imparted to the anticancer effect when HNHA is co-administered, HNHA; cisplatin; lenvatinib; co-administration of cisplatin and HNHA (Cisplatin+HNHA; C+H); After co-administration of lenvatinib and HNHA (Lenvatinib+HNHA; L+H), the number of cancer cells over time was analyzed by MTT assay, and the results are shown in FIGS. 1 to 3 .
도 1에서 보는 바와 같이, 대장암 세포주인 HT-29에 HNHA나 시스플라틴을 단독으로 처리한 경우에 비하여 이들을 병용으로 처리한 경우(C+H) 상기 대장암 세포주의 세포 수가 더욱 감소한 것을 확인할 수 있었다. 또한, 시스플라틴과 HNHA를 병용 처리한 경우(C+H)가 렌바티닙과 HNHA를 병용 처리한 경우(L+H)에 비하여 HT-29 대장암 세포주의 세포 수 감소 효과가 현저히 뛰어난 것을 확인할 수 있었다. 한편, 렌바티닙을 단독으로 처리한 경우는 다른 항암제를 처리한 경우보다 HT-29 대장암 세포주 사멸에 큰 효과가 없음을 알 수 있었다.As shown in FIG. 1 , it was confirmed that the number of cells in the colorectal cancer cell line was further reduced when the colorectal cancer cell line HT-29 was treated with HNHA or cisplatin alone, compared to the case where they were treated in combination (C + H). . In addition, it was confirmed that the cell number reduction effect of the HT-29 colorectal cancer cell line was significantly better when cisplatin and HNHA were combined (C+H) than when lenvatinib and HNHA were combined (L+H). there was. On the other hand, it was found that the case where lenvatinib was treated alone had no significant effect on the killing of the HT-29 colon cancer cell line compared to the case where other anticancer drugs were treated.
도 2에서 보는 바와 같이, 환자로부터 유래된 재발성 대장암 세포주인 YUMC-C1 세포에 HNHA나 시스플라틴을 단독으로 처리한 경우에 비하여 이들을 병용으로 처리한 경우(C+H)에 상기 재발성 대장암 세포주의 세포 수가 현저히 감소한 것을 확인할 수 있었고, 렌바티닙을 단독으로 처리한 경우나 렌바티닙과 HNHA를 병용 처리한 경우(L+H)에 비하여서도 재발성 대장암 세포주의 세포 수 감소 효과가 현저히 뛰어난 것을 확인할 수 있었다. As shown in FIG. 2 , when YUMC-C1 cells, a recurrent colorectal cancer cell line derived from a patient, were treated with HNHA or cisplatin alone, they were treated in combination (C+H). It was confirmed that the number of cells in the cell line was significantly reduced, and the effect of reducing the number of cells in the recurrent colorectal cancer cell line was lower than that of lenvatinib alone or combined treatment with lenvatinib and HNHA (L+H). It was confirmed that it was remarkably excellent.
도 3에서 보는 바와 같이, 환자로부터 유래된 전이성 대장암 세포주인 YUMC-C2 세포에 HNHA나 시스플라틴을 단독으로 처리한 경우에 비하여 이들을 병용으로 처리한 경우(C+H) 상기 전이성 대장암 세포주의 세포 수가 현저히 감소한 것을 확인할 수 있었다. 또한, 시스플라틴과 HNHA를 병용 처리한 경우(C+H)가 렌바티닙을 단독으로 처리한 경우나 렌바티닙과 HNHA를 병용 처리한 경우(L+H)에 비하여 전이성 대장암 세포주의 세포 수 감소 효과가 현저히 뛰어난 것을 확인할 수 있었다. As shown in FIG. 3 , when YUMC-C2 cells, a metastatic colorectal cancer cell line derived from a patient, were treated in combination with HNHA or cisplatin compared to the case where they were treated alone (C+H), the cells of the metastatic colorectal cancer cell line It can be seen that the number is significantly reduced. In addition, the number of cells in metastatic colorectal cancer cell lines when cisplatin and HNHA were treated in combination (C+H) compared to when lenvatinib was treated alone or when lenvatinib and HNHA were treated in combination (L+H) It was confirmed that the reduction effect was remarkably excellent.
상기 실시예들을 통하여 본 발명에 따른 시스플라틴과 HNHA의 조합은 대장암, 특히는 항암제 내성 대장암, 재발성 대장암 또는 전이성 대장암에 효과적인 치료제로 사용될 수 있음을 알 수 있다. Through the above examples, it can be seen that the combination of cisplatin and HNHA according to the present invention can be used as an effective therapeutic agent for colorectal cancer, particularly anticancer drug-resistant colorectal cancer, recurrent colorectal cancer, or metastatic colorectal cancer.
이상에서 본 발명의 실시예에 대하여 상세하게 설명하였지만 본 발명의 권리범위는 이에 한정되는 것은 아니고, 청구범위에 기재된 본 발명의 기술적 사상을 벗어나지 않는 범위 내에서 다양한 수정 및 변형이 가능하다는 것은 당 기술분야의 통상의 지식을 가진 자에게는 자명할 것이다.Although the embodiments of the present invention have been described in detail above, the scope of the present invention is not limited thereto, and various modifications and variations are possible within the scope without departing from the technical spirit of the present invention described in the claims. It will be apparent to those of ordinary skill in the art.
본 발명은 암의 예방 또는 치료용 약학적 조성물에 관한 것으로, 보다 상세하게는 암 세포 뿐만 아니라, 내성 암, 재발성 암 또는 전이성 암 세포주의 성장을 억제할 수 있는 약학적 조성물에 관한 것이다. The present invention relates to a pharmaceutical composition for the prevention or treatment of cancer, and more particularly, to a pharmaceutical composition capable of inhibiting the growth of not only cancer cells, but also resistant cancer, recurrent cancer or metastatic cancer cell lines.

Claims (19)

  1. 히스톤 탈아세틸화 저해제(Histone Deacetylation inhibitor; HDAC inhibitor) 및 시스플라틴(Cisplatin)을 유효 성분으로 포함하는 암의 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating cancer comprising a histone deacetylation inhibitor (HDAC inhibitor) and cisplatin as active ingredients.
  2. 제1항에 있어서, According to claim 1,
    상기 히스톤 탈아세틸화 저해제는 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용되는 염인, 약학적 조성물:The histone deacetylation inhibitor is a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition:
    [화학식 1][Formula 1]
    Figure PCTKR2021006348-appb-I000002
    Figure PCTKR2021006348-appb-I000002
  3. 제1항에 있어서, According to claim 1,
    상기 히스톤 탈아세틸화 저해제는 상기 조성물 내에 1μM 내지 20μM 농도로 포함되는 것인, 약학적 조성물.The histone deacetylation inhibitor will be included in the composition at a concentration of 1 μM to 20 μM, the pharmaceutical composition.
  4. 제1항에 있어서, According to claim 1,
    상기 시스플라틴은 상기 조성물 내에 10μM 내지 200μM 농도로 포함되는 것인, 약학적 조성물.The cisplatin will be included in the composition at a concentration of 10 μM to 200 μM, the pharmaceutical composition.
  5. 제1항에 있어서, According to claim 1,
    상기 히스톤 탈아세틸화 저해제와 상기 시스플라틴은 1:1~100의 몰비로 포함되는, 약학적 조성물. The histone deacetylation inhibitor and the cisplatin are included in a molar ratio of 1:1 to 100, a pharmaceutical composition.
  6. 제1항에 있어서, According to claim 1,
    상기 암은 유방암, 담도암, 담낭암, 췌장암, 대장암, 자궁암, 식도암, 위암, 뇌암, 직장암, 폐암, 방광암, 신장암, 난소암, 전립선암, 자궁암, 두경부암, 피부암, 혈액암 및 간암으로 이루어진 군으로부터 선택되는 1종 이상인, 약학적 조성물. The cancer is breast cancer, biliary tract cancer, gallbladder cancer, pancreatic cancer, colorectal cancer, uterine cancer, esophageal cancer, stomach cancer, brain cancer, rectal cancer, lung cancer, bladder cancer, kidney cancer, ovarian cancer, prostate cancer, uterine cancer, head and neck cancer, skin cancer, blood cancer and liver cancer At least one selected from the group consisting of, a pharmaceutical composition.
  7. 제6항에 있어서, 7. The method of claim 6,
    상기 암은 대장암인, 약학적 조성물. The cancer is colon cancer, pharmaceutical composition.
  8. 히스톤 탈아세틸화 저해제(Histone Deacetylation inhibitor; HDAC inhibitor) 및 시스플라틴(Cisplatin)을 유효 성분으로 포함하는 내성 암, 재발성 암 또는 전이성 암의 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating resistant cancer, recurrent cancer, or metastatic cancer, comprising a histone deacetylation inhibitor (HDAC inhibitor) and cisplatin as active ingredients.
  9. 제8항에 있어서, 9. The method of claim 8,
    상기 히스톤 탈아세틸화 저해제는 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용되는 염인, 약학적 조성물:The histone deacetylation inhibitor is a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition:
    [화학식 1][Formula 1]
    Figure PCTKR2021006348-appb-I000003
    Figure PCTKR2021006348-appb-I000003
  10. 제8항에 있어서, 9. The method of claim 8,
    상기 히스톤 탈아세틸화 저해제는 상기 조성물 내에 1μM 내지 20μM 농도로 포함되는 것인, 약학적 조성물.The histone deacetylation inhibitor will be included in the composition at a concentration of 1 μM to 20 μM, the pharmaceutical composition.
  11. 제8항에 있어서, 9. The method of claim 8,
    상기 시스플라틴은 상기 조성물 내에 10μM 내지 200μM 농도로 포함되는 것인, 약학적 조성물.The cisplatin will be included in the composition at a concentration of 10 μM to 200 μM, the pharmaceutical composition.
  12. 제8항에 있어서, 9. The method of claim 8,
    상기 히스톤 탈아세틸화 저해제와 상기 시스플라틴은 1:1~100의 몰비로 포함되는, 약학적 조성물. The histone deacetylation inhibitor and the cisplatin are included in a molar ratio of 1:1 to 100, a pharmaceutical composition.
  13. 제8항에 있어서, 9. The method of claim 8,
    상기 암은 유방암, 담도암, 담낭암, 췌장암, 대장암, 자궁암, 식도암, 위암, 뇌암, 직장암, 폐암, 방광암, 신장암, 난소암, 전립선암, 자궁암, 두경부암, 피부암, 혈액암 및 간암으로 이루어진 군으로부터 선택되는 1종 이상인, 약학적 조성물. The cancer is breast cancer, biliary tract cancer, gallbladder cancer, pancreatic cancer, colorectal cancer, uterine cancer, esophageal cancer, stomach cancer, brain cancer, rectal cancer, lung cancer, bladder cancer, kidney cancer, ovarian cancer, prostate cancer, uterine cancer, head and neck cancer, skin cancer, blood cancer and liver cancer At least one selected from the group consisting of, a pharmaceutical composition.
  14. 제13항에 있어서, 14. The method of claim 13,
    상기 암은 대장암인, 약학적 조성물. The cancer is colon cancer, pharmaceutical composition.
  15. 제8항에 있어서,9. The method of claim 8,
    상기 내성 암은 항암제에 내성을 갖는 암인, 약학적 조성물.The resistant cancer is a cancer having resistance to an anticancer agent, a pharmaceutical composition.
  16. 제8항에 있어서, 9. The method of claim 8,
    상기 전이성 암은 암세포가 간, 폐, 뼈, 림프절 또는 복강으로 전이된 것인, 약학적 조성물.The metastatic cancer is that the cancer cells have metastasized to the liver, lung, bone, lymph node or abdominal cavity, a pharmaceutical composition.
  17. 히스톤 탈아세틸화 저해제(Histone Deacetylation inhibitor; HDAC inhibitor) 및 시스플라틴(Cisplatin)을 유효 성분으로 포함하는 암 줄기세포(Cancer Stem CELL, Tumor Initiating Cells; CSC, TICs)의 성장 억제용 약학적 조성물.A pharmaceutical composition for inhibiting the growth of cancer stem cells (Cancer Stem CELL, Tumor Initiating Cells; CSC, TICs) comprising histone deacetylation inhibitor (HDAC inhibitor) and cisplatin as active ingredients.
  18. 투여가 필요한 개체에게 히스톤 탈아세틸화 저해제(Histone Deacetylation inhibitor; HDAC inhibitor) 및 시스플라틴(Cisplatin)을 유효량으로 투여하는 단계를 포함하는, 암의 예방 또는 치료 방법. A method for preventing or treating cancer, comprising administering an effective amount of a histone deacetylation inhibitor (HDAC inhibitor) and cisplatin to an individual in need of administration.
  19. 투여가 필요한 개체에게 히스톤 탈아세틸화 저해제(Histone Deacetylation inhibitor; HDAC inhibitor) 및 시스플라틴(Cisplatin)을 유효량으로 투여하는 단계를 포함하는, 내성 암, 재발성 암 또는 전이성 암의 예방 또는 치료 방법. A method for preventing or treating resistant cancer, recurrent cancer, or metastatic cancer, comprising administering an effective amount of a histone deacetylation inhibitor (HDAC inhibitor) and cisplatin (Cisplatin) to an individual in need of administration.
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