WO2011068386A2 - Composition anti-cancer contenant un composé kempféride comme ingrédient actif - Google Patents

Composition anti-cancer contenant un composé kempféride comme ingrédient actif Download PDF

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WO2011068386A2
WO2011068386A2 PCT/KR2010/008648 KR2010008648W WO2011068386A2 WO 2011068386 A2 WO2011068386 A2 WO 2011068386A2 KR 2010008648 W KR2010008648 W KR 2010008648W WO 2011068386 A2 WO2011068386 A2 WO 2011068386A2
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cancer
compound
camphoride
anticancer
present
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WO2011068386A3 (fr
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이민재
박대훈
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강원대학교산학협력단
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37—Coumarins, e.g. psoralen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention relates to a composition for anticancer containing a kaempferide compound as an active ingredient. More specifically, the present invention relates to an anticancer composition containing a camphoride compound as an active ingredient, a medicament for preventing or treating cancer, and a functional health food.
  • Cancer is one of the incurable diseases to be solved by humankind, and huge capital is being invested in the development to cure it all over the world.In Korea, it is the number one disease cause of death among Koreans since the 1990s. More than 100,000 people have been diagnosed with cancer, and more than 60,000 have died.
  • the cancer causing factors include smoking, ultraviolet rays, chemicals, food, stress, and other environmental factors, but the causes of the various causes are difficult to develop the treatment, and the effects of the treatment vary depending on the site of occurrence.
  • Surgical treatment is effective for eliminating the initial state of cancer, but in some cases, it is necessary to remove organs.
  • metastasis cannot be prevented, and radiation treatment has a high therapeutic effect in treating cancer of a specific site, while radiation therapy cannot prevent new carcinogenesis and metastasis. The problem is that it involves pain.
  • anticancer agent which is a chemotherapeutic agent used for the treatment of malignant tumors
  • anticancer agents are agents that exhibit anticancer activity by inhibiting various metabolic pathways of cancer cells, especially synthesis of nucleic acids.
  • anticancer drugs currently used in cancer treatment are classified into six categories of alkylating agents, metabolic antagonists, antibiotics, mitosis inhibitors, hormonal agents, and other agents according to biochemical mechanisms of action. It does not work but damages normal cells, especially tissue cells with active cell division, which has been accompanied by various side effects such as bone marrow dysfunction, gastrointestinal disorders, and alopecia. Therefore, it is very important to develop an anticancer agent that can enhance the anticancer effect without any side effects of the human body.
  • the research is to extract or process anticancer ingredients from natural materials such as plants to develop them into cancer treatments, preventive medicines or health supplements. Is actively being done.
  • the anticancer activity of the anticancer agent for the treatment of cancer can be divided in several ways from the cancer development mechanism, firstly the mechanisms that induce direct action on cancer cells, ie cytotoxicity, cell cycle regulation and apoptosis (apoptosis) The second is due to the mechanism of inhibiting the angiogenesis of cancer cells, the third is due to the mechanism of inhibiting the invasion of cancer cells, and the fourth is to increase the immunity to inhibit the metastasis of cancer cells. It can be divided into mechanism and the like.
  • each anticancer agent may be active at each of these stages, but it is common to show anticancer activity by showing a major activity at a specific stage.
  • the present inventors completed the present invention by confirming that the camphoride compound has not only an excellent anticancer activity but also no side effects during the study for developing a new anticancer agent.
  • an object of the present invention is to provide an anticancer composition containing a camphoride compound or a salt thereof as an active ingredient which is excellent in anticancer activity and has no side effects.
  • Another object of the present invention to provide a medicament for the prevention or treatment of cancer comprising the anticancer composition.
  • Another object of the present invention to provide a functional health food having an anticancer effect including the anticancer composition.
  • the present invention is effective to a camphoride (kaempferide: 3,5,7-trihydroxy-4'-methoxyflavone) compound represented by the formula (1) or a pharmaceutically acceptable salt thereof It provides the anticancer composition containing as a component.
  • camphoride kaempferide: 3,5,7-trihydroxy-4'-methoxyflavone
  • the camphoride compound may have an activity of inhibiting cell proliferation or inducing apoptosis of cancer cells.
  • the camphoride compound may be included in a concentration of 0.1 ⁇ 0.5mM relative to the total volume of the composition.
  • the cancer is breast cancer, laryngeal cancer, lung cancer, epithelial cancer, prostate cancer, esophageal cancer, pancreatic cancer, colon cancer, liver cancer, gastric cancer, tongue cancer, skin cancer, brain tumor, uterine cancer, cervical cancer, ovarian cancer, kidney cancer , Gallbladder cancer, oral cancer, colon cancer, liver cancer and bladder cancer.
  • the present invention also provides a medicament for the prevention or treatment of cancer comprising the anticancer composition according to the present invention.
  • the present invention provides a functional health food having an anticancer effect including the anticancer composition according to the present invention.
  • the camphoride compound according to the present invention has excellent activity of inhibiting cell proliferation of cancer cells, and excellent activity of inducing apoptosis by apoptosis, and has no side effects on the body, thereby preventing or treating cancer. And it is very useful as a material of the functional health food having an anticancer effect.
  • FIG. 1 shows a chromatogram obtained by separating and purifying a camphoride compound of the present invention by performing C18 HPLC chromatography.
  • Figure 2 shows the peak confirming whether the compound purchased on the market through the 1 H NMR analysis of the camphoride compound.
  • Figure 3 is a graph showing the degree of apoptosis by FACs method through the treatment of 0.1% DMSO and 0.33 mM of the camphoride compound of the present invention as a control for the breast cancer cell line MDA-MB-231 as a control .
  • FIG. 4 is a photograph showing the degree of migration of NF- ⁇ B to the nucleus through a fluorescence microscope after treatment with 0.1% DMSO and 7ug / ml of the camphoride compound against MDA-MB-231, a breast cancer cell line.
  • Figure 5a shows a photograph of the expression level of COX-2 in breast cancer cell line through a fluorescence microscope after treatment with 0.1% DMSO and 7ug / ml camperide compound for MDA-MB-231 breast cancer cell line.
  • FIG. 5B shows COX in breast cancer cells via Western blot with anti-COX-2 antibody after treatment with 0.1% DMSO, 7ug / ml and 70ug / ml camphoride compounds, respectively, for MDA-MB-231, a breast cancer cell line. It shows that the expression level of -2 was confirmed.
  • the present invention is characterized in that it provides an anticancer composition containing a camphoride compound or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the camphoride compound according to the present invention may be 3,5,7-trihydroxy-4'-methoxyflavone represented by the following formula (3,5,7-trihydroxy-4'-methoxyflavone).
  • the camphoride compound having the above structural formula according to the present invention may be used in the form of a salt, preferably a pharmaceutically acceptable salt.
  • the salt is preferably an acid addition salt formed by a pharmaceutically acceptable free acid, and an organic acid and an inorganic acid may be used as the free acid.
  • the organic acid is not limited thereto, citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, metasulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, Glutamic acid and aspartic acid.
  • the inorganic acid includes, but is not limited to, hydrochloric acid, bromic acid, sulfuric acid and phosphoric acid.
  • camphoride compound according to the present invention may be isolated from nature or manufactured and used by chemical synthesis methods known in the art, or may be used as long as it is a commercially available camphoride compound.
  • the camphoride compound of the present invention when isolated and purified from nature, it can be obtained from natural materials by using a method of extracting and separating conventional substances, and the extraction for separating and purifying camphoride compound from nature
  • the method may use a solvent extraction method through water or an organic solvent.
  • the organic solvent is not limited thereto, but methanol, ethanol, propanol, isopropanol, isopropanol, butanol, acetone, ether, ether, and benzene
  • Various solvents such as benzene, chloroform, ethyl acetate, methylene chloride, hexane and cyclohexane may be used alone or in combination.
  • the extract obtained from the above method can be used to obtain the active ingredient from the extract using a separation and purification method known in the art, generally, various synthetic resins such as silica gel or activated alumina Column chromatography and high performance liquid chromatography (HPLC) packed with may be used alone or in combination. Extraction and separation and purification of the active ingredient is not necessarily limited to the above-described method.
  • camphoride compounds have been found to have melanin synthesis inhibitory effect, antioxidant effect and blood pressure control effect (Matsuda, H. et. Al., Bioorg Med Chem ., 17, 6048 , 2009; Simoes, LMC, et.al. , J. Ethnopharm , 94, 59, 2004; Maruyama, H. et.al., Biol Pharm Bull , 32, 7, 1244, 2009).
  • these camphoride components have anticancer activity by inhibiting cell proliferation of cancer cells and inducing apoptosis has not been known until now.
  • the present invention first identified that the camphoride compound has excellent anticancer activity.
  • the camphoride compound according to the present invention is characterized by having anticancer activity through cell death by apoptosis (apoptosis) while inhibiting cell proliferation of cancer cells.
  • cancer is characterized by "uncontrolled growth and proliferation of cells", and the growth and proliferation of these abnormal cells form cell masses called tumors, which form into the surrounding tissues. In severe cases, the disease may spread to other organs in the body and cause abnormal activity of normal cells. Therefore, inhibition of abnormal cell growth and proliferation is one of the methods for preventing and treating cancer.
  • Apoptosis also refers to active death caused by the regulation and expression of several genes and proteins in response to a programmed signal within the cell. It is eliminated by phagocytosis such as macrophage and does not cause inflammation.
  • phagocytosis such as macrophage and does not cause inflammation.
  • morphological and physiological characteristics of apoptosis include cytoplasm shrinkage, membrane blebbing, chromatin condensation, DNA fragmentation, and phosphatidylserine, lipids that form the cell membrane. (phosphatidylserine) exposure to the outside of the cell and the formation of atoptosome (apoptome) has been reported.
  • apoptosis can be confirmed by various methods, such as a method for confirming DNA fragmentation characteristic of apoptosis through electrophoresis, TUNEL assay (terminal dUTP nick-end labeling assay) or Flow cytometry method using Annexin V is generally used.
  • Annexin V has a property of binding to phosphatidylserine (PS), which is present in a large amount in the cell membrane, at the initial stage of apoptosis.
  • PS phosphatidylserine
  • necrosis is a passive death that occurs rapidly due to changes in the external environment, which leads to the process of irregular clumping and swelling of cytoplasm, and finally the degradation of cells.
  • Cell debris are produced and are known to cause inflammation (Earnshaw, WC, Curr. Opin. Cell Biol ., 7, pp 337-343, 1995).
  • apoptosis or cell death through apoptosis is easily observed in many normal physiological phenomena of life.
  • apoptosis is a function of various morphogenesis and functional functions of the immune or nervous system observed in the early stages of life. It plays an important role in the functional self-organization process. In addition, after adulthood it also plays an essential role in tissue homeostasis, regulation of cell numbers, removal of damaged cells and defense mechanisms against infection.
  • apoptosis is deeply involved in the development of various diseases, that is, the occurrence of abnormal cell death may be the cause of neurodegenerative disorders, immune disorders and cardiovascular diseases. Abnormal inhibition of apoptosis can cause cancer.
  • apoptosis plays an important role in maintaining the normal physiological function of life, and is closely related to the pathogenesis of various diseases, and apoptosis of each cell constituting an individual is genetically damaged cells or differentiation stimulants. It is a mechanism that can remove abnormal cells in order to prevent tumors developed by inappropriate induction of differentiation.
  • a substance having an activity that inhibits the proliferation and growth of abnormal cells and induces apoptosis can be used as an anticancer agent (Fesus, L., J. Cell Biochem. , 22, 151-161, 1995; Reddy, BS, Cancer Res ., 57, 420-425, 1997).
  • the camphoride compound is a breast cancer cell line MDA-MB-231 cells and MCF-7 cells and prostate cancer cell line PC-3
  • the extent of inhibition of proliferation of cancer cells by the camphoride compound was confirmed by the FACs method.
  • cell proliferation of MDA-MB-231 and MCF-7 cells, which are breast cancer cell lines, and PC-3 cells, which are prostate cancer cell lines were inhibited.
  • about 80% of MDA-MB-231, a breast cancer cell line was inhibited. Showed high cell proliferation inhibition (see Table 1).
  • the camphoride of the present invention is very excellent in anticancer activity.
  • the cancer cell line is treated with a camphoride compound, and stained with annexin V, a label of apoptosis, to apoptosis.
  • apoptosis-induced apoptosis was significantly increased in the breast cancer cells treated with the camphoride compound compared to the control treated with DMSO instead of the camphoride compound. It was shown to be proportionally dependent on concentration (see FIG. 3).
  • the camphoride compound of the present invention has anticancer activity by inducing apoptosis through apoptosis in cancer cells.
  • camphoride compound according to the present invention is characterized by having anticancer activity by a mechanism through inhibition of NF- ⁇ B and COX-2.
  • NF- ⁇ B the development and progression of tumors are known to be closely related to the signal transduction process by NF- ⁇ B.
  • activation of NF- ⁇ B inhibits apoptosis of cancer cells. It has been shown to promote cell proliferation by promoting progression (Monks NR et al ., J. Cell Biochem , 92, 646-650, 2004), and phosphorylated active NF- ⁇ B is a cyclooxygenase-2. Has been shown to promote the expression of genes.
  • recent studies have reported that NF- ⁇ B and I ⁇ B exist in phosphorylated and activated form in cancer cells, and activated NF- ⁇ B migrates from the cytoplasm to the nucleus (Jand BC., J. BioL . Chem ., 275, 39 507-39515, 2000; Monks NR et al ., J. Cell Biochem , 92, 646-650, 2004).
  • COX-2 cyclooxygenase-2
  • COX-2 cyclooxygenase-2
  • COX-2 cyclooxygenase-2
  • COX-2 cyclooxygenase-2
  • COX-2 is a main enzyme involved in the biosynthesis of prostaglandin, and there are two kinds of isomers in vivo.
  • COX-1 is expressed in the normal state and is involved in gastrointestinal protection and renal function control.
  • COX-2 is transient and rapid in the cell by mitogen or cytokines during inflammation or other immune reactions. Expressed.
  • substances that inhibit COX-1 or COX-2 may play an important role not only in the treatment of inflammation but also in inhibiting cancer production.
  • inhibiting the activity or expression of NF- ⁇ B and COX-2 can inhibit the development or progression of cancer.
  • the present inventors examined whether the camphoride compound according to the present invention has an activity of inhibiting NF- ⁇ B and COX-2, and when the camphoride compound was treated in breast cancer cell lines, NF- ⁇ B shifted to the nucleus and COX. The expression of -2 was shown to be more inhibited than the control group not treated with the camphoride compound (see Example 4).
  • the present inventors measured the degree of apoptosis due to necrosis when measuring the degree of apoptosis after treatment with camphoride in cancer cells to confirm whether the camphoride compound of the present invention is stable as a clinical anticancer agent. As a result of comparison with the control group, the degree of necrosis by camperide treatment was found to be almost similar to the control group (see FIG. 3).
  • camphoride compound according to the present invention can be used as an anticancer agent having relatively good stability without causing other side effects in vivo.
  • the present invention provides an anticancer composition containing a camphoride compound or a pharmaceutically acceptable salt thereof as an active ingredient, and the camphoride compound may be included at a concentration of 0.1 to 0.5 mM with respect to the total volume of the composition.
  • composition of the present invention can be used as a pharmaceutical composition for preventing and treating the symptoms of cancer caused by abnormal growth and proliferation of cells.
  • the type of cancer that can be prevented or treated using the camphoride compound is not limited thereto, but is not limited thereto, breast cancer, laryngeal cancer, lung cancer, epithelial cancer, prostate cancer, esophageal cancer, pancreatic cancer, colon cancer, liver cancer, gastric cancer, tongue cancer, Skin cancer, brain tumor, uterine cancer, cervical cancer, ovarian cancer, kidney cancer, gallbladder cancer, oral cancer, colon cancer, liver cancer and bladder cancer.
  • the anticancer composition according to the present invention may include a pharmaceutically effective amount of a camphoride compound alone or may include one or more pharmaceutically acceptable carriers, excipients or diluents.
  • the pharmaceutically effective amount herein refers to an amount sufficient to prevent, ameliorate and treat cancer.
  • the pharmaceutically effective amount of the camphoride compound according to the invention is 0.5-100 mg / day / kg body weight, preferably 0.5-5 mg / day / kg body weight.
  • the pharmaceutically effective amount may be appropriately changed according to the degree of disease symptoms, the age, weight, health condition, sex, route of administration and duration of treatment of the patient.
  • the pharmaceutically acceptable means a composition that is physiologically acceptable and does not cause an allergic reaction such as gastrointestinal disorder, dizziness or similar reaction when administered to a human.
  • carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, Polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers and preservatives may be further included.
  • compositions of the present invention may be formulated using methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal.
  • the formulations may be in the form of powders, granules, tablets, emulsions, syrups, aerosols, soft or hard gelatin capsules, sterile injectable solutions, sterile powders.
  • the anticancer composition according to the present invention may be administered through various routes including oral, transdermal, subcutaneous, intravenous or intramuscular, and the dosage of the active ingredient is determined by the route of administration, the age, sex, weight and severity of the patient. It may be appropriately selected depending on several factors.
  • the anticancer composition of the present invention can be administered in parallel with known compounds having the effect of preventing, improving or treating the symptoms of cancer.
  • the present invention may provide a medicament for preventing or treating cancer, including a composition containing a camphoride compound or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the composition of the present invention comprising the same has a very stable feature for the body.
  • the anticancer composition of the present invention can be added to a food for the purpose of preventing or improving cancer, and thus the composition of the present invention can be used as a functional health food composition having an anticancer effect.
  • composition for functional health foods having an anticancer effect of the present invention can be easily utilized as foods, such as the main ingredients, side ingredients, food additives, functional foods or beverages that are effective in preventing and improving cancer symptoms.
  • the term “food” refers to a natural product or processed product containing one or more nutrients, and preferably means a state in which it can be directly eaten through a certain processing step, It includes all foods, food additives, functional foods and drinks.
  • Foods to which the composition for functional health foods having an anticancer effect according to the present invention can be added include, for example, various foods, beverages, gums, teas, vitamin complexes, and functional foods.
  • food includes special nutritional products (e.g., formulated milk, young, infant food, etc.), processed meat products, fish products, tofu, jelly, noodles (e.g. ramen, noodles, etc.), bread, health supplements, seasonings.
  • Foods e.g. soy sauce, miso, red pepper paste, mixed soy sauce
  • sauces confectionery (e.g. snacks), candy, chocolates, gums, ice creams, dairy products (e.g.
  • fermented milk, cheese, etc. other processed foods
  • kimchi, Pickled foods various kimchi, pickles, etc.
  • beverages e.g., fruit drinks, vegetable drinks, soy milk, fermented beverages, etc.
  • natural seasonings e.g. ramen soup, etc.
  • the food, beverage or food additives may be prepared by a conventional manufacturing method.
  • the term "functional food” refers to the control of biological defense rhythms and disease prevention of food groups or food compositions that have added value to the food by using physical, biochemical, or biotechnological techniques to act and express the function of the food for a specific purpose. It means a food that is designed and processed to fully express the body's regulatory function regarding recovery and the like, and specifically, it may be a health functional food.
  • the functional food may include food acceptable food additives, and may further include appropriate carriers, excipients and diluents commonly used in the manufacture of functional foods.
  • the "beverage” refers to a generic term for drinking to quench thirst or to enjoy a taste and includes a functional drink.
  • the beverage contains, as essential ingredients, a composition for the prevention and amelioration of the cancer symptoms as an essential ingredient, and there are no particular restrictions on the other ingredients, and may contain various flavors or natural carbohydrates as additional ingredients, such as ordinary drinks. Can be.
  • the food containing the functional health food composition having an anticancer enhancing effect of the present invention in addition to the above-described flavors, colorants and fillers such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors (Cheese, chocolate, etc.), pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks, and the like.
  • the above components may be used independently or in combination.
  • the amount of the composition according to the present invention may be included in 0.001% to 90% by weight of the total food weight, preferably 0.1% by weight To 40% by weight, and in the case of a beverage, it may be included in a ratio of 0.01g to 20g, preferably 0.3g to 10g based on 100ml, but for health and hygiene purposes or for health control purposes.
  • the active ingredient is not limited to the above range because it can be used in an amount above the above range because there is no problem in terms of safety.
  • the present inventors have performed a C18 HPLC chromatography to determine the correct this campesterol fluoride compound a compound purchased for campesterol fluoride compound a commercially available separating campesterol fluoride compound, known in the art with a discrete compound 1 H-NMR analysis was performed.
  • camphoride compound was a camphoride (kaempferide: 3,5,7-trihydroxy-4'-methoxyflavone) having a molecular weight of 300.26 represented by the following Chemical Formula 1, and was separated by C18 HPLC chromatography.
  • the peaks for the camphoride compound were shown in FIG. 1, and the peaks of the camphoride compound by 1 H-NMR are shown in FIG. 2.
  • the activity of inhibiting cell proliferation of cancer cells with respect to the camphoride compound identified in Example 1 was investigated through FACs known in the art.
  • MDA-MB-231 cell line and MCF-7 cell line and PC-3 cell line, prostate cancer cell line which were purchased from Korea Cell Line Bank as cancer cells, were treated with 10% fetal bovine serum, 2mg / ml sodium carbonate, 100 Cultured in RPMI-1640 (Gibco / BRL, Grand Island, NY) medium containing U / mL penicillin and 100 / mL of streptomycin, each cancer cell line incubated thereafter was 1.5 ⁇ 10 4 cells / After dispensing into wells, the camphoride compound was treated at various concentrations of 0.01 to 0.33 mM and then incubated for 48 hours.
  • A is the OD value of the control cell
  • B is the OD value of the cells treated with the camphoride compound.
  • * indicates that P ⁇ 0.001 by Tukey's studentized range (HSD) test, calculated by calculating the cell activity of the control to 100%.
  • the camphoride compound isolated and purified in the present invention inhibits cell proliferation against MDA-MB-231 and MCF-7 cells, which are breast cancer cell lines, and PC-3 cells, which are prostate cancer cell lines. It can be seen that there is an effect, and in particular, the breast cancer cell line MDA-MB-231 was found to have the activity of inhibiting the proliferation of cells with very high efficiency.
  • the present inventors confirmed that the camphoride compound according to the present invention has anticancer activity through cytotoxicity and cytotoxicity of various cancer cells.
  • the present inventors investigated whether the camphoride compound has an activity of inducing apoptosis of cancer cells in order to directly confirm the anticancer activity of the camphoride compound.
  • 0.33mM camphoride compound was treated with MDA-MB-231 cell line, which was cultured under the conditions of Example 2, and cultured for 48 hours.
  • the camphoride compound of the present invention has excellent activity of killing cells by inducing apoptosis in cancer cells.
  • the present inventors when using the camphoride compound as an anticancer agent, in order to confirm the stability to the body, the degree of apoptosis due to necrosis when treated with camphoride compound compared to the control group, the control group was about 3.07% Necrosis rate of was shown, and even when treated with camphoride compound showed a necrosis rate of about 4.0% similar to the control.
  • camphoride compound according to the present invention is biologically stable through the fact that the degree of cell death by necrosis does not show a significant difference from the control group.
  • the present inventors found that the camphoride compound not only has the activity of inhibiting the cell proliferation of cancer cells and induces apoptosis by apoptosis, but also has no side effects and is excellent in stability so that it can ultimately be used as a therapeutic agent for effective cancer treatment.
  • the camphoride compound not only has the activity of inhibiting the cell proliferation of cancer cells and induces apoptosis by apoptosis, but also has no side effects and is excellent in stability so that it can ultimately be used as a therapeutic agent for effective cancer treatment.
  • NF- ⁇ B which acts as a survival factor of cancer cells, is known to regulate COX-2 gene expression while migrating to the nucleus when activated by phosphorylation. Therefore, the present inventors examined whether the camphoride compound was treated with breast cancer cells to inhibit NF- ⁇ B activity, that is, to inhibit migration to the nucleus.
  • MDA-MB-231 cells which are breast cancer cell lines, were dispensed to 100 ⁇ plate at 1.0 ⁇ 10 6 cells / well and cultured for 24 hours. Thereafter, 7ug / ml of the camphoride compound was treated, and after 90 minutes of incubation, migration of NF- ⁇ B to the nucleus was observed by immunofluorescence analysis. At this time, the immunofluorescence assay method was performed by washing the cells treated with camphoride with cold PBS solution, fixing with cold acetone solution, and using animal-free-blocker (Vector, Burlingame, CA, USA, SP-5030). Blocking for hours was followed by overnight reaction at 4 ° C.
  • animal-free-blocker Vector, Burlingame, CA, USA, SP-5030
  • NF- ⁇ B migration to the nucleus was suppressed in the breast cancer cells treated with the camphoride compound as compared with the control group.
  • the camphoride compound of the present invention has anticancer activity through the mechanism of inhibiting migration of NF- ⁇ B, which is a survival factor of cancer cells, into cancer cells in cancer cell lines.
  • the inventors performed western blot and immunofluorescence assays to investigate whether the camphoride compound has an activity of inhibiting the expression of COX-2, which is known to mediate inflammatory reactions and grow cancer cells in cancer cells.
  • the immunofluorescence assay was performed by incubating the camphoride-treated MDA-MB-231 cells for 48 hours in the same manner as in Example ⁇ 4-1>, and then centrifuging to obtain the cells, followed by 3 steps with cold PBS solution. Washed once, cells were fixed with 4% formaldehyde (Sigma Aldrich, SO57504) and then washed three times with cold PBS solution.
  • MDA-MB-231 cells were aliquoted to 100 ⁇ plate at 1.0 ⁇ 10 6 cells / well, followed by incubation for 24 hours, and 7, 70 ug each of the camphoride compound for the cells. / ml, then incubated for 48 hours, cells were removed from the plate with trypsin and washed with cold PBS solution. Thereafter, to confirm the expression of COX-2 in the cells, the cells' lysates were electrophoresed with 10% SDS-PAGE, followed by anti-COX-2 polyclonal antibody (Cayman, Ann Arbor, MI, USA). Blotting was performed by Western blotting method known in the art using Cat # CAY-160106.
  • a DMSO-treated group was used instead of the camphoride compound, and a beta-actin monoclonal antibody (Sigma Aldrich, USA, Cat # A-5316) was used to confirm the amount of the same protein in Western blot.
  • the present inventors have found that the camphoride compound of the present invention has an effect of inhibiting the growth of NF- ⁇ B and simultaneously inhibiting cancer growth by inhibiting the expression of COX-2. It was found that the camphoride compound can be used as a therapeutic agent for the prevention or treatment of cancer.

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Abstract

La présente invention concerne une composition anti-cancer contenant un composé kempféride comme ingrédient actif. Plus spécifiquement, la présente invention concerne une composition anti-cancer contenant un composé kempféride présentant la structure de la formule chimique I comme ingrédient actif. La composition anti-cancer selon la présente invention présente l'avantage de pouvoir être utilisée avec un très bon effet comme substance pour des médicaments destinés à la prévention et au traitement du cancer ainsi que dans des aliments sanitairement fonctionnels, parce que non seulement elle exerce une remarquable action de suppression de la prolifération des cellules cancéreuses en induisant la mort des cellules par apoptose mais aussi parce qu'elle n'entraîne pas d'effets secondaires pour l'organisme.
PCT/KR2010/008648 2009-12-04 2010-12-03 Composition anti-cancer contenant un composé kempféride comme ingrédient actif WO2011068386A2 (fr)

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KR10-2009-0119539 2009-12-04
KR1020090119539A KR20110062726A (ko) 2009-12-04 2009-12-04 캄페라이드 화합물을 유효성분으로 함유하는 항암용 조성물

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KR20210021827A (ko) * 2019-08-19 2021-03-02 연세대학교 산학협력단 켐페라이드를 유효성분으로 포함하는 대사질환의 예방 또는 치료용 조성물

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
E. SZLISZKA ET AL.: 'Ethanolic extract of propolis (EEP) enhances the apoptosis-inducing potential of TRAIL in cancer cells' MOLECULES vol. 14, no. 2, 13 February 2009, ISSN 1420-3049 pages 738 - 754 *
J. B. DASKIEWICZ ET AL.: 'Effects of flavonoids on cell proliferation and caspase activation in a human colonic cell line HT29: An SAR study' JOURNAL OF MEDICINAL CHEMISTRY vol. 48, no. 8, 2005, ISSN 0022-2623 pages 2790 - 2804 *
R. VACLAVIKOVA ET AL.: 'Modulation of paclitaxel transport by flavonoid derivatives in human breast cancer cells. Is there a correlation between binding affinity to NBD of P-gp and modulation of transport?' BIOORGANIC & MEDICINAL CHEMISTRY vol. 14, no. 13, 2006, ISSN 0968-0896 pages 4519 - 4525 *

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