KR101774905B1 - Composition for preventing or treating cancer comprising otobaphenol - Google Patents

Abstract

The present invention relates to a composition for preventing or treating cancer comprising otobaphenol as an effective component. Otobaphenol according to the present invention has an excellent effect of inhibiting the activity of pyruvate dehydrogenase kinase and inhibiting the growth of cancer cells, and thus can be effectively used for preventing, ameliorating or treating cancer.

Description

[0001] The present invention relates to a composition for preventing or treating cancer comprising, as an active ingredient,

The present invention relates to a composition for preventing or treating cancers containing autobaphenol as an active ingredient.

Tumor usually refers to a mass that is abnormally raised by autonomous overgrowth of the body tissue, and can be divided into benign tumor and malignant tumor. While benign tumors are relatively slow to grow and do not metastasize (move away from where the tumor originally originated), malignant tumors grow rapidly, infiltrating the surrounding tissues, spread or spread to each part of the body, Threatening. Therefore, malignant tumors can be thought of in the same sense as cancer.

Cells, the smallest unit of the body, normally divide and grow by the regulating function of the cells themselves, and when they reach the end of their life or become damaged, they die (die off) themselves and maintain an overall number balance. However, if there is a problem with the regulation function of these cells due to various reasons, abnormal cells that normally should die are over-proliferated. In some cases, they penetrate into surrounding tissues and organs to form masses, Destroying or transforming the cancer, such a condition can be defined as cancer.

Although normal cells produce energy-causing ATP through the TCA cycle, cancer cells are known to have a specific metabolic process that produces a large amount of ATP even in the hypoxic state, mainly using the corresponding process without going through the TCA cycle. Metabolic pathology improves the growth of cancer cells in both aerobic and anaerobic conditions (Tennant et al., Nat Rev Cancer, 2010). In addition, it has been proposed that cancer cells produce a large amount of lactate through lactic acid fermentation by pyruvate produced through the process through this specific metabolic process, thereby acidifying the tissues around the cancer cells to create a favorable environment for cancer cells In particular, lactic acid released into the vicinity of cancer cells inhibits extracellular matrix degradation, which is an important characteristic of cancer cells, and inhibits immune cell activity, that is, the activity of NK cells (natural killer cells), and cytotoxic T lymphocytes T lymphocytes, CTL) and cytokine production and activity. It also activates hypoxia-inducible factor (HIF), which promotes metastasis and angiogenesis, thereby maintaining the characteristics of malignant tumors. Since pyruvic acid plays a role as a gate to distinguish between cancer and normal cell metabolism during the process of cancer metabolism, the degradation of pyruvate dehydrogenase (PDH), a key enzyme in the metabolism of pyruvate, is an important biochemical key to cancer metabolism It is known. Pyruvate dehydrogenase kinase (PDHK) phosphorylates pyruvate dehydrogenase, which degrades the enzymatic function of pyruvate dehydrogenase kinase (PDHK). As a result, it inhibits the entry of pyruvic acid into the TCA cycle, It is becoming a key enzyme. Recently, research has been actively conducted to develop a new concept of cancer treatment that kills cancer cells by inhibiting the function of pyruvate dehydrogenase (CRC) enzyme (Le et al., Clin Cancer Res.

On the other hand, otobaphenol is a kind of lignan initially isolated in nutmeg ( Myristica fragrans Houtt.) (Phytother Res 2006, 20 (8): 680), bulls blood ( Iryanthera juruensis Warb .; Rev. Bol. Quim 2006, 23 (1)), janggyeongnam Schisandra (Kadsura longipedunculata FINET et GAGNEP) and was found to be the major component in such plants (Chem Pharm Bull 2008, 56 ( 8...): 1143). Antioxidant activity (Antioxid Redox Signal 2003, 5 (3): 281), inhibition of protein tyrosine dephosphate 1B (Phytother Res 2006, 20 (8): 680) (Nat Prod Commun. 2011, 6 (2): 231) have been reported, but there have been no reports on the function of autobaphenol associated with the inhibition of cancer cells.

The inventors of the present invention, while studying a method of effectively inhibiting cancer cell proliferation and promoting apoptosis, confirmed that the activity of carbinobenzoic acid inhibits the activity of pyruvate dehydrogenase kinase and inhibits cancer cell growth, Completed.

It is an object of the present invention to provide a pharmaceutical composition for the prevention or treatment of cancer containing autobaphenol as an active ingredient.

It is also an object of the present invention to provide a food composition for preventing or ameliorating a cancer containing an autophenol as an active ingredient.

In order to accomplish the above object, the present invention provides a pharmaceutical composition for preventing or treating cancer containing autobaphenol as an active ingredient.

In addition, the present invention provides a food composition for preventing or ameliorating cancer containing autobaphenol as an effective ingredient.

The autophenol according to the present invention inhibits the activity of pyruvate dehydrogenase kinase and has an excellent effect of inhibiting the growth of cancer cells, and thus can be effectively used for preventing, ameliorating or treating cancer.

FIG. 1 is a graph showing the degree of phosphorylation of pyruvate dehydrogenase A after the treatment with autobaphenol of the present invention through western blotting in vitro. FIG.
FIG. 2 is a graph showing the degree of phosphorylation of pyruvate dehydrogenase A after autobaphenol treatment of the present invention by Western blotting in cells. FIG.
FIG. 3 is a graph showing the results of confirming the cancer cell growth inhibitory effect of carboplatin-treated cells of the present invention through cell viability. FIG.
FIG. 4 is a graph showing the results of confirming and comparing the cancer cell growth inhibitory effect of the present invention on the cell viability after treating the extracts of autobaphenol and nutmeg respectively.

The present invention provides a composition for preventing or treating cancer comprising as an active ingredient otobaphenol.

The composition comprises a pharmaceutical composition or a food composition.

Hereinafter, the present invention will be described in detail.

The active ingredient of the present invention, autobaphenol, can be obtained from natural products by conventional extraction and fractionation methods, or synthesized by an organic synthesis method or by purchasing commercially available reagents.

Phenol motorcycle of the present invention is a kind of lignan _{C 19 H 20 O 4 ((} 8R, 8'R, 7R) -4'-hydroxy-5'-methoxy-3,4-methylenedioxy-2 ', 7,8, 8'-neolignan) represented by the following formula (1).

[Chemical Formula 1]

The autobaphenol inhibits pyruvate dehydrogenase phosphorylation by inhibiting the function of pyruvate dehydrogenase kinase.

Phosphorylation of pyruvate dehydrogenase kinase plays an important role in the sugar metabolism of cancer, and the activity of pyruvate dehydrogenase is inhibited by the active hyperactivation of pyruvate dehydrogenase kinase in cancer cells. It is known that the expression of pyruvate dehydrogenase kinase 1 (PDHK-1) is increased by transcriptional regulatory proteins such as MYC or HIF-1, and pyruvate dehydrogenase complex is inactivated by phosphorylating the serine residue of pyruvic acid dehydrogenase.

Examples of the cancer include a brain tumor, a benign astrocytoma, a malignant astrocytoma, a pituitary adenoma, a meningioma, a brain lymphoma, an oliguria, a cervicitis, a cranial tumor, a brain tumor, a head and neck tumor, a laryngeal cancer, Thyroid cancer, mediastinal tumor, esophageal cancer, breast cancer, male breast cancer, abdominal tumor, stomach cancer, hepatic cancer, gallbladder cancer, biliary cancer, pancreatic cancer, small intestine cancer, small intestine cancer, non-small cell lung cancer, The present invention relates to a method for the treatment and prophylaxis of cancer, colon cancer, anal cancer, bladder cancer, kidney cancer, male genital tumor, penile cancer, urethral cancer, prostate cancer, female genital tumor, cervical cancer, endometrial cancer, ovarian cancer, uterine sarcoma, Female cancer of the urethra, skin cancer, myeloma, leukemia and malignant lymphoma, and the like.

The composition of the present invention may contain at least one known active ingredient having an anticancer effect together with autopepanol.

The composition of the present invention may further comprise, in addition to the above-described effective ingredient for administration, a pharmaceutically acceptable carrier, excipient or diluent. Examples of carriers, excipients or diluents usable in the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil. The pharmaceutical composition according to the present invention can be formulated in the form of oral, granule, tablet, capsule, suspension, emulsion, syrup, aerosol or the like oral preparation, external preparation, suppository and sterilized injection solution according to a conventional method Can be used. In the case of formulation, it may be prepared using diluents or excipients such as fillers, extenders, binders, humectants, disintegrants, surfactants and the like which are generally used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose sucrose, lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. The liquid preparation for oral administration can be formulated into a formulation such as a suspension, a solution, an emulsion, and a syrup. In addition to water and liquid paraffin which are commonly used simple diluents, various excipients such as a wetting agent, a sweetening agent, , Preservatives, and the like. Further, it can be suitably formulated according to each disease or ingredient, using appropriate methods in the art or by the method disclosed in Remington's Pharmaceutical Science (recent edition), Mack Publishing Company, Easton PA.

The term "administering" as used herein is meant to provide any desired composition of the invention to an individual by any suitable method.

The composition of the present invention may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically) depending on the intended method, and the dose may be appropriately determined depending on the patient's weight, age, , Diet, administration time, method of administration, excretion rate, and severity of the disease. The dose of autobaphenol is 0.1 to 100 mg / m 2 / day. It is preferable to administer it 1 to 4 cycles twice a week, but it is not limited thereto.

The pharmaceutical composition of the present invention may be administered to the individual by various routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intra-uterine or intravaginal injection.

The composition of the present invention can be used alone or in combination with methods for the prevention or treatment of cancer or using surgery, hormone therapy, drug therapy and biological response modifiers.

The active ingredient of the present invention may be added to a health functional food for the purpose of preventing or improving cancer. In the present invention, the term "health functional food" refers to a food having a biological control function such as prevention and improvement of disease, bio-defense, immunity, recovery of disease and aging inhibition.

When the autobaphenol of the present invention is used as a food additive, the autobaphenol may be directly added or used together with other food or food ingredients, and may be appropriately used according to a conventional method. The amount of the active ingredient to be mixed can be suitably determined according to the intended use (prevention, health or therapeutic treatment). In general, the active ingredient of the present invention is added in an amount of not more than 15% by weight, preferably not more than 10% by weight based on the raw material in the production of food or beverage. However, in the case of long-term intake for the purpose of health and hygiene or for the purpose of controlling health, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount exceeding the above range.

There is no particular limitation on the kind of the food. Examples of the foods to which the above substances can be added include dairy products including meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen noodles, gums, ice cream, various soups, drinks, tea, Alcoholic beverages, and vitamin complexes, all of which include health foods in a conventional sense.

The health beverage composition of the present invention may contain various flavors or natural carbohydrates as an additional ingredient such as ordinary beverages. The natural carbohydrates may be monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, natural sweeteners such as dextrin and cyclodextrin, synthetic sweeteners such as saccharine and aspartame, and the like. The ratio of the natural carbohydrate is generally about 0.01 to 10 g, preferably about 0.01 to 0.1 g per 100 ml of the composition of the present invention.

In addition to the above, the composition of the present invention may further contain various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, A carbonating agent used in a carbonated beverage, and the like. In addition, the composition of the present invention may comprise flesh for the production of natural fruit juices, fruit juice drinks and vegetable drinks. These components may be used independently or in combination. Although the ratio of such additives is not critical, it is generally selected in the range of 0.01 to 0.1 parts by weight per 100 parts by weight of the composition of the present invention.

Hereinafter, preferred examples for the understanding of the present invention will be described. However, the following experimental examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the experimental examples.

Experimental Example  1. of autobaphenol Pyruvic acid  Dehydrogenase Kinase  Identification of the activity inhibition effect

1-1. Confirmed in vitro

In order to confirm whether or not autobaphenol inhibits the activity of pyruvate dehydrogenase kinase, the following experiment was conducted.

First, pyruvate dehydrogenase A (PDHA) and adenosine triphosphate (ATP), which are substrates thereof, were added to pyruvate dehydrogenase phosphorylase (PDHK) dissolved in a buffer solution in a test tube, autobaphenol was treated by concentration, The reaction was carried out in a constant temperature water bath for 30 minutes. Thereafter, the degree of phosphorylation of pyruvate dehydrogenase A, which is a substrate of pyruvate dehydrogenase kinase, was confirmed by Western blotting, and the results are shown in FIG.

As shown in Fig. 1, it was confirmed that autobaphenol effectively inhibited the activity of pyruvate dehydrogenase from about 300 μM.

1-2. Identification within the cell

In order to confirm whether or not the autobaphenol inhibits the activity of pyruvate dehydrogenase kinase in actual cells, the following experiment was conducted.

First, human colon cancer cells, DLD1, were cultured, treated with autobaphenol at different concentrations, and cultured for 4 hours. Then, the cells were disrupted to extract proteins, and the degree of phosphorylation of pyruvate dehydrogenase A was confirmed by Western blotting. The results are shown in FIG.

As shown in Fig. 2, it was confirmed that autobaphenol effectively inhibited the activity of pyruvate dehydrogenase from 10 μM concentration.

Experimental Example  2. Autobaphenol  Cell growth inhibition effect on cancer cells

(MDA-MB231), leukemia cell line (K562), colon cancer cell line (HT29), hepatocellular carcinoma cell line (Hep3B), colon cancer cell line (DLD1), lung cancer (H460), prostate cancer cell line (DU145), neuroblastoma (SH-SY5Y) and gastric cancer cell line (SNU-620) were inoculated on a 96-well plate and autobaphenol was treated by concentration. The cell viability was then measured and analyzed. The results are shown in FIG.

(MDA-MB231), leukemia cell line (K562), colon cancer cell line (HT29), liver cancer cell line (Hep3B), colon cancer cell line (DLD1), lung cancer cell line (H460), prostate cancer cell line It was confirmed that the growth of various cancer cells such as DU145, neuroblastoma (SH-SY5Y) and gastric cancer cell line (SNU-620) was effectively inhibited at a concentration of 10 to 30 μM.

Experimental Example  3. Autobaphenol  Comparison of Cell Growth Inhibitory Effect on Cancer Cells

(MDA-MB231), a leukemia cell line (K562), a colon cancer cell line (HT29), a hepatocellular carcinoma cell line (Hep3B), and a hepatocellular carcinoma cell line And colorectal cancer cell line (DLD1) were inoculated in a 96-well plate and treated with autobaphenol by concentration. The control group was treated with the nutmeg extract containing the active substance having chemical structure similar to that of autobaphenol and known to have anticancer effect. Cell viability was then measured and compared with the control group. The results are shown in FIG.

As shown in FIG. 4, in the breast cancer cell line (MDA-MB231), leukemia cell line (K562), colorectal cancer cell line (HT29), liver cancer cell line (Hep3B) and colon cancer cell line (DLD1) The survival rate of the cells was significantly lower and the IC50 value was lower. It was found that the autobaphenol increased the growth of breast cancer cell line (MDA-MB231), leukemia cell line (K562), colon cancer cell line (HT29), hepatocarcinoma cell line (Hep3B) And thus, it is confirmed that the anti-cancer effect is remarkably superior to that of the nutmeg extract containing similar chemicals.

From the above experimental results, it was confirmed that the autobaphenol according to the present invention inhibits the activity of the pyruvate dehydrogenase kinase and has an excellent effect of inhibiting cancer cell growth.

Hereinafter, formulation examples of the pharmaceutical composition containing the composition of the present invention will be described, but the present invention is not intended to be limited but is specifically described.

Formulation example  1. Preparation of pharmaceutical preparations

1-1. Manufacture of tablets

3.5 g

Amlodipine 4mg

100 mg of corn starch

100 mg of milk

Magnesium stearate 2 mg

After mixing the above components, tablets were prepared by tableting according to the usual preparation method of tablets.

1-2. Preparation of capsules

3.5 g

Amlodipine 4mg

Corn starch 50 mg

50 mg of milk

Magnesium stearate 2 mg

After mixing the above components, they were filled in gelatin capsules according to the conventional preparation method of capsules to prepare capsules.

1-3. Injection preparation

3.5 g

Amlodipine 4mg

3.0 mg of sodium metabisulfite

Methylparaben 0.8 mg

Propyl paraben 0.1 mg

Sterile sterilized water for injection

Injection was prepared by mixing the above components per ampoule (2 mL) according to the usual injection preparation method.

Formulation example  2. Manufacture of food preparation

2-1. Manufacture of health food

100 mg of autobaphenol

Vitamin mixture quantity

70 g of vitamin A acetate

Vitamin E 1.0 mg

Vitamin B1 0.13 mg

0.15 mg of vitamin B2

Vitamin B6 0.5 mg

0.2 g of vitamin B12

Vitamin C 10 mg

Biotin 10 g

Nicotinic acid amide 1.7 mg

Folate 50 g

Calcium pantothenate 0.5 mg

Mineral mixture quantity

1.75 mg of ferrous sulfate

0.82 mg of zinc oxide

Magnesium carbonate 25.3 mg

Potassium monophosphate 15 mg

Secondary calcium phosphate 55 mg

Potassium citrate 90 mg

Calcium carbonate 100 mg

Magnesium chloride 24.8 mg

Although the composition ratio of the above-mentioned vitamin and mineral mixture is comparatively mixed with a composition suitable for health food as a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional method for producing healthy foods , Granules can be prepared and used in the manufacture of health food compositions according to conventional methods.

2-2. Health drink  Produce

100 mg of autobaphenol

Vitamin C 15 g

Vitamin E (powder) 100 g

19.75 g of ferrous lactate

3.5 g of zinc oxide

Nicotinic acid amide 3.5 g

Vitamin A 0.2 g

Vitamin B1 0.25 g

Vitamin B2 0.3g

Water quantification

The above components were mixed according to a conventional health drink manufacturing method, and the mixture was stirred and heated at 85 DEG C for about 1 hour. The solution thus prepared was filtered and sterilized in a sterilized 2 L container, It is used in the production of the health beverage composition of the invention.

Although the compositional ratio is relatively mixed with a component suitable for a favorite drink, it is also possible to arbitrarily modify the compounding ratio according to the regional or national preference such as the demand class, the demanding country, and the use purpose.

Claims (6)

A pharmaceutical composition for preventing or treating cancer containing otobaphenol as an active ingredient. The pharmaceutical composition for preventing or treating cancer according to claim 1, wherein the autobaphenol is represented by the following formula (1).
[Chemical Formula 1]

The method of claim 1, wherein the cancer is selected from the group consisting of brain tumor, benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, brain lymphoma, oligodendroglioma, intracranial, cytoplasm, brain stem tumor, head and neck tumor, laryngeal cancer, Thyroid cancer, breast cancer, breast cancer, male breast cancer, gastric cancer, hepatic cancer, gallbladder cancer, bile duct cancer, non-small cell lung cancer, Pancreatic cancer, small intestine cancer, colorectal cancer, anal cancer, bladder cancer, kidney cancer, male genital tumor, penile cancer, urethral cancer, prostate cancer, female genital tumor, cervical cancer, endometrial cancer, ovarian cancer, uterine sarcoma, vaginal cancer, female external Wherein the cancer is one or more selected from the group consisting of germ cell cancer, female urethral cancer, skin cancer, myeloma, leukemia, and malignant lymphoma. The pharmaceutical composition for preventing or treating cancer according to claim 1, wherein the autobaphenol inhibits the activity of pyruvate dehydrogenase kinase. A food composition for prevention or improvement of cancer containing autobaphenol as an active ingredient. 6. The food composition according to claim 5, wherein the autobaphenol is represented by the following formula (1).
[Chemical Formula 1]

Images