Composition for inhibiting cancer cell growth, composition for anti-cancer treatment, composition for inhibiting canceration of normal cells, composition for inhibiting cancer onset, and composition for inducing cancer cell death

Abstract

An objective of the present invention is to suppress the canceration of cells and the progression of malignant cancer, i.e., the onset of cancer, and to induce cell death in cancer cells. The present invention provides a composition for inhibiting the proliferation of cancer cells, an anti-cancer composition, a composition for inhibiting the canceration of normal cells, a composition for inhibiting the onset of cancer, and a composition for inducing cancer cell death, each containing at least one of turmeronol A and turmeronol B as an active ingredient.

Description

Technical Field

[0001] The present invention relates to a composition for suppressing the growth of cancer cells, an anti-cancer composition, a composition for suppressing the carcinogenesis of normal cells, a composition for suppressing the onset of cancer, and a composition for inducing cancer cell death.

Background Art

[0002] The process leading to death from cancer has been analyzed in detail and is being clarified. Currently, a cancer progression process called multistage carcinogenesis has been proposed. This is where genes are damaged by exposure to chemicals, radiation, or viruses, mutations occur in multiple genes such as oncogenes and tumor suppressor genes, and the accumulation of these abnormalities causes cells to become cancerous. After acquiring various abnormal properties such as cell proliferation, the cells acquire the ability to invade, metastasize, and recur, becoming more malignant (malignant progression) and eventually leading to death. Therefore, suppressing the carcinogenesis of cells due to chemical, radiation, or virus-induced gene mutations is important for preventing cancer, and inhibiting the growth, invasion, and metastasis of cancer cells is considered important for suppressing the malignant progression of cancer.

[0003] Patent Document 1 describes an antitumor agent containing a protein-binding polysaccharide isolated from the rhizome of turmeric as an active ingredient.

[0004] On the other hand, Turmeronol A and Turmeronol B are known components isolated from turmeric and their structures have been determined (Non-Patent Document 1). Non-Patent Document 1 reports that Turmeronol A has an effect of inhibiting the enzyme activity of soybean lipoxygenase and an antioxidant effect.

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Non-Patent Documents

[0006]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0007] Patent Document 1 describes the action of a protein-bound polysaccharide isolated from the rhizome of turmeric, and Non-Patent Document 1 describes the antioxidant action of tumeronol A. However, in these documents, it is not described that tumeronol A and tumeronol B derived from turmeric suppress the carcinogenesis of cells and the progression of malignancy of cancer, that is, the onset of cancer, or induce cancer cell death.

[0008] Therefore, the present invention provides means for suppressing the carcinogenesis of cells and the progression of malignancy of cancer, that is, the onset of cancer, and means for inducing cancer cell death.

Means for Solving the Problems

[0009] The present inventors have found that tumeronol A and tumeronol B can suppress the carcinogenesis of cells and the progression of malignancy of cancer, that is, the onset of cancer, and can induce cancer cell death, and have thus completed the following present invention. (1) A composition for suppressing the growth of cancer cells, containing at least one of tumeronol A and tumeronol B as an active ingredient. (2) The composition for suppressing the growth of cancer cells according to (1), wherein the cancer cells are colorectal cancer cells. (3) An anti-cancer composition containing at least one of tumeronol A and tumeronol B as an active ingredient. (4) The anti-cancer composition according to (3), which is an anti-cancer composition for colorectal cancer. (5) A composition for suppressing the carcinogenesis of normal cells, containing at least one of tumeronol A and tumeronol B as an active ingredient. (6) The composition for suppressing the carcinogenesis of normal cells into colorectal cancer according to (5), which suppresses the carcinogenesis of normal cells. (7) A composition for suppressing cancer development, containing at least one of thermonol A and thermonol B as an active ingredient. (8) The composition for suppressing cancer development according to (7), which is a composition for suppressing cancer development against colorectal cancer. (9) A composition for inducing cancer cell death, containing at least one of thermonol A and thermonol B as an active ingredient. (10) The composition for inducing cancer cell death according to (9), wherein the cancer cell is a colorectal cancer cell.

[0010] (11) Use of at least one of thermonol A and thermonol B for the manufacture of a composition for suppressing the growth of cancer cells. (12) Use of at least one of thermonol A and thermonol B for the manufacture of a medicament for suppressing the growth of cancer cells. (13) Administering at least one of thermonol A and thermonol B to cancer cells, in vivo or in vitro, and suppressing the growth of the cancer cells A method for suppressing the growth of cancer cells, comprising the above. (14) Thermonol A, thermonol B, or a mixture of thermonol A and thermonol B for suppressing the growth of cancer cells, in vivo or in vitro. (15) The use according to (11), the use according to (12), the method according to (13), or thermonol A, thermonol B, or a mixture of thermonol A and thermonol B according to (14), wherein the cancer cell is a colorectal cancer cell.

[0011] (16) Use of at least one of thermonol A and thermonol B for the manufacture of an anti-cancer composition. (17) Use of at least one of thermonol A and thermonol B for the manufacture of an anti-cancer medicament. Administering at least one of termenol A and termenol B to a patient in need of cancer treatment, and treating cancer in said patient A method for treating cancer, comprising. (19) Termenol A, termenol B, or a mixture of termenol A and termenol B for treating cancer in a patient in need of cancer treatment. (20) The use according to (16), the use according to (17), the method according to (18), or the termenol A, termenol B, or a mixture of termenol A and termenol B according to (19), wherein the cancer is colorectal cancer.

[0012] (21) Use of at least one of termenol A and termenol B for the manufacture of a composition for suppressing carcinogenesis of normal cells. (22) Use of at least one of termenol A and termenol B for the manufacture of a medicament for suppressing carcinogenesis of normal cells. (23) Administering at least one of termenol A and termenol B to normal cells, in vivo or in vitro, and suppressing carcinogenesis of said normal cells A method for suppressing carcinogenesis of normal cells, comprising. (24) Termenol A, termenol B, or a mixture of termenol A and termenol B for suppressing carcinogenesis of normal cells, in vivo or in vitro. (25) The use according to (21), the use according to (22), the method according to (23), or the termenol A, termenol B, or a mixture of termenol A and termenol B according to (24), wherein the carcinogenesis is carcinogenesis to colorectal cancer.

[0013] (26) Use of at least one of termenol A and termenol B for the manufacture of a composition for suppressing cancer onset. (27) Use of at least one of termenol A and termenol B for the manufacture of a medicament for suppressing cancer onset. (28) Administering at least one of termenol A and termenol B to a patient in need of suppressing the onset of cancer, and suppressing the onset of cancer in said patient A method for suppressing the onset of cancer, comprising the above. (29) Termenol A, termenol B, or a mixture of termenol A and termenol B for suppressing the onset of cancer in a patient in need of suppressing the onset of cancer. (30) The use according to (26), the use according to (27), the method according to (28), or the termenol A, termenol B, or a mixture of termenol A and termenol B according to (29), wherein the cancer is colorectal cancer.

[0014] (31) Use of at least one of termenol A and termenol B for the manufacture of a composition for inducing cancer cell death. (32) Use of at least one of termenol A and termenol B for the manufacture of a medicament for inducing cancer cell death. (33) Administering at least one of termenol A and termenol B to cancer cells, in vivo or in vitro, and inducing cell death of said cancer cells A method for inducing cancer cell death, comprising the above. (34) Termenol A, termenol B, or a mixture of termenol A and termenol B for inducing cancer cell death, in vivo or in vitro. (35) The use according to (31), the use according to (32), the method according to (33), or the termenol A, termenol B, or a mixture of termenol A and termenol B according to (34), wherein the cancer cells are colorectal cancer cells.

[0015] This specification incorporates the disclosure of Japanese Patent Application No. 2018-093848, which is the basis of the priority of this application.

Advantages of the Invention

[0016] The present invention provides a composition for inhibiting the growth of cancer cells, an anti-cancer composition, a composition for inhibiting the canceration of normal cells, a composition for inhibiting the onset of cancer, and a composition for inducing cancer cell death, which contains at least one of tumeronol A and tumeronol B as an active ingredient.

Brief Description of the Drawings

[0017]

Figure 1

Figure 2

Modes for Carrying Out the Invention

[0018] <Active ingredient> Tumeronol A and tumeronol B are compounds having the following planar structures, respectively.

[0019]

Chemical formula

[0020]

Chemical formula

[0021] The natural turmericol A and turmericol B isolated from turmeric are known to have an S configuration at the 6-position carbon in the partial structure of 2-methyl-2-hepten-4-one, respectively. However, the turmericol A and turmericol B that can be used in the present invention only need to have the above planar structure, and are not limited to the turmericol A and turmericol B having a steric structure derived from turmeric. Preferably, they are the turmericol A and turmericol B having a steric structure derived from turmeric. In the present invention, various forms of turmericol A and turmericol B such as salts and hydrates can be used. As the salts of turmericol A and turmericol B, there is no particular limitation as long as they are pharmaceutically acceptable salts. For example, sodium salts (sodium salts of phenolic hydroxyl groups) can be mentioned.

[0022] In each aspect of the present invention, the active ingredient is at least one of turmericol A and turmericol B. That is, the active ingredient may consist only of turmericol A, may consist only of turmericol B, or may be a mixture of turmericol A and turmericol B.

[0023] The active ingredient used in the present invention may be derived from plants or may be artificially synthesized. For example, optically active (+)-turmericol A can be synthesized by the method described in Biosci Biotechnol Biochem. 1993;57(7):1137-40.

[0024] The active ingredient used in the present invention is more preferably derived from a plant raw material, and more preferably from a plant of the genus Curcuma in the Zingiberaceae family. Examples of plants of the genus Curcuma in the Zingiberaceae family include Curcuma longa (turmeric), Curcuma aromatica, Curcuma zedoaria, Curcuma phaeocaulis, Curcuma kwangsiensis, Curcuma wenyujin, and Curcuma xanthorrhiza, and particularly preferably Curcuma longa (turmeric). Turmeronol A and turmeronol B can be obtained from parts such as the rhizomes of plants of the genus Curcuma in the Zingiberaceae family. The rhizomes may be those collected from the soil, and those in which an appropriate part of the rhizome is used as it is, or cut into appropriate dimensions or shapes, or in the form of a pulverized product can be used. The plant raw material may be appropriately dried.

[0025] At least one compound selected from turmeronol A and turmeronol B used in the present invention can be in any form such as in the form of a plant or plant processed product containing it, in the form of an extract extracted from a plant or plant processed product, in the form of a fraction with increased purity of the compound prepared from the extract, or in the form of the compound isolated from the extract or fraction.

[0026] As the extraction solvent used for the preparation of an extract containing at least one selected from tumeronol A and tumeronol B from plants or plant processed products, at least one selected from the group consisting of water, polar organic solvents, and non-polar organic solvents, and supercritical fluids such as supercritical carbon dioxide can be exemplified. As at least one extraction solvent selected from the group consisting of water, polar organic solvents, and non-polar organic solvents, water, polar organic solvents, a mixed solvent of water and polar organic solvents, non-polar organic solvents, etc. can be exemplified. The polar organic solvent may be a mixed solvent of a plurality of polar organic solvents. The non-polar organic solvent may be a mixed solvent of a plurality of non-polar organic solvents. "Water" includes hot water. As hot water, for example, hot water at 95°C or higher can be used. As the polar organic solvent, at least one alcohol (which may be a mixed solvent of a plurality of alcohols) can be mentioned. The alcohol is not particularly limited, but methanol and ethanol are preferred. When using a mixed solvent of alcohol and water as the extraction solvent, the mixing ratio is not particularly limited, but for example, a range of 10:90 to 90:10 by weight is preferred, and a range of 20:80 to 50:50 is more preferred. The extraction method of at least one selected from tumeronol A and tumeronol B from plants or plant processed products is not particularly limited. The extract containing at least one selected from tumeronol A and tumeronol B is used after volatilizing and removing the extraction solvent as necessary.

[0027] The method for preparing a fraction with increased purity of at least one selected from tumeronol A and tumeronol B from the extract is not particularly limited. For example, an extract containing at least one compound selected from tumeronol A and tumeronol B is subjected to liquid-liquid partitioning of ethyl acetate / water, and a method for purifying the above to a high purity in the ethyl acetate fraction, or a method for purifying the compound to a high purity by subjecting the extract or fraction to chromatography such as column chromatography can be exemplified. As the chromatography, reverse phase column chromatography, normal phase thin layer chromatography, etc. can be used.

[0028] The method for isolating at least one compound selected from turmeronol A and turmeronol B from the extract or fraction is not particularly limited, and a method for isolating the compound using means such as chromatography can be used.

[0029] At least one compound selected from turmeronol A and turmeronol B, a plant or processed plant product containing the compound, or an extract or fraction of a plant or processed plant product containing the compound may be processed by conventional methods such as drying, powdering, granulating, solubilizing, etc.

[0030] <Composition for inhibiting cancer cell growth, composition for anti - cancer, composition for inhibiting canceration of normal cells, composition for inhibiting cancer onset, composition for inducing cancer cell death> The first aspect of the present invention relates to a composition for inhibiting cancer cell growth containing at least one selected from turmeronol A and turmeronol B as an active ingredient. The composition for inhibiting cancer cell growth of the present invention is preferably a composition for inhibiting the growth of colorectal cancer cells. The first aspect of the present invention also relates to the use of at least one selected from turmeronol A and turmeronol B for the manufacture of a composition for inhibiting cancer cell growth. The first aspect of the present invention also relates to the use of at least one selected from turmeronol A and turmeronol B for the manufacture of a medicament for inhibiting cancer cell growth. The first aspect of the present invention also relates to a method for inhibiting cancer cell growth, which includes administering at least one selected from turmeronol A and turmeronol B to cancer cells in vivo or in vitro, and inhibiting the growth of the cancer cells. The first aspect of the present invention also relates to turmeronol A, turmeronol B, or a mixture of turmeronol A and turmeronol B for inhibiting cancer cell growth in vivo or in vitro.

[0031] The second aspect of the present invention relates to a composition for cancer treatment, containing at least one selected from turmeronol A and turmeronol B as an active ingredient. The composition for cancer treatment of the present invention is preferably a composition for cancer treatment against colorectal cancer. The second aspect of the present invention also relates to the use of at least one selected from turmeronol A and turmeronol B for the manufacture of a composition for cancer treatment. The second aspect of the present invention also relates to the use of at least one selected from turmeronol A and turmeronol B for the manufacture of a medicament for cancer treatment. The second aspect of the present invention also relates to a method for treating cancer, including administering at least one selected from turmeronol A and turmeronol B to a patient in need of cancer treatment and treating cancer in said patient. The second aspect of the present invention also relates to at least one selected from turmeronol A and turmeronol B for treating cancer in a patient in need of cancer treatment.

[0032] The third aspect of the present invention relates to a composition for suppressing carcinogenesis of normal cells, containing at least one selected from turmeronol A and turmeronol B as an active ingredient. The composition for suppressing carcinogenesis of normal cells of the present invention preferably suppresses the carcinogenesis of normal cells into colorectal cancer. The third aspect of the present invention also relates to the use of at least one selected from turmeronol A and turmeronol B for the manufacture of a composition for suppressing carcinogenesis of normal cells. The third aspect of the present invention also relates to the use of at least one selected from turmeronol A and turmeronol B for the manufacture of a medicament for suppressing carcinogenesis of normal cells. The third aspect of the present invention also relates to a method for suppressing carcinogenesis of normal cells, including administering at least one selected from turmeronol A and turmeronol B to normal cells in vivo or in vitro and suppressing the carcinogenesis of said normal cells. The third aspect of the present invention also relates to at least one selected from turmeronol A and turmeronol B for suppressing carcinogenesis of normal cells in vivo or in vitro.

[0033] The fourth aspect of the present invention relates to a composition for suppressing cancer onset, which contains at least one selected from turmeronol A and turmeronol B as an active ingredient. The composition for suppressing cancer onset of the present invention is preferably a composition for suppressing cancer onset against colorectal cancer. The fourth aspect of the present invention also relates to the use of at least one selected from turmeronol A and turmeronol B for the manufacture of a composition for suppressing cancer onset. The fourth aspect of the present invention also relates to the use of at least one selected from turmeronol A and turmeronol B for the manufacture of a medicament for suppressing cancer onset. The fourth aspect of the present invention also relates to a method for suppressing cancer onset, which includes administering at least one selected from turmeronol A and turmeronol B to a patient in need of suppressing cancer onset and suppressing cancer onset in the patient. The fourth aspect of the present invention also relates to at least one selected from turmeronol A and turmeronol B for suppressing cancer onset in a patient in need of suppressing cancer onset.

[0034] The fifth aspect of the present invention relates to a composition for inducing cancer cell death, which contains at least one selected from turmeronol A and turmeronol B as an active ingredient. The composition for inducing cancer cell death of the present invention is preferably a composition for inducing cell death of colorectal cancer cells. The fifth aspect of the present invention also relates to the use of at least one selected from turmeronol A and turmeronol B for the manufacture of a composition for inducing cancer cell death. The fifth aspect of the present invention also relates to the use of at least one selected from turmeronol A and turmeronol B for the manufacture of a medicament for inducing cancer cell death. The fifth aspect of the present invention also relates to a method for inducing cancer cell death, which includes administering at least one selected from turmeronol A and turmeronol B to cancer cells in vivo or in vitro and inducing cell death of the cancer cells. The fifth aspect of the present invention also relates to at least one selected from turmeronol A and turmeronol B for inducing cancer cell death in vivo or in vitro.

[0035] The active ingredient used in the present invention, or a composition or medicine containing the same, may be a composition in various forms such as pharmaceuticals, foods and drinks, feeds, food additives, feed additives, etc., and is more preferably a pharmaceutical or a food and drink. Foods and drinks also include those in the forms of foods with functional claims, foods for specified health uses, supplements for nutritional supplementation, etc. The composition or medicine containing the active ingredient used in the present invention is preferably in the form of a composition that is ingested or administered orally or nasally, and more preferably in the form of a composition that is ingested or administered orally.

[0036] The composition or medicine containing the compound according to one embodiment of the present invention contains at least one selected from termenol A and termenol B such that the total amount of termenol A and termenol B is 100 μg or more per daily intake or dosage, preferably per daily intake or dosage for one human, particularly one adult. The composition or medicine containing the active ingredient according to another embodiment of the present invention contains at least one selected from termenol A and termenol B such that termenol A is 80 μg or more and / or termenol B is 20 μg or more per daily intake or dosage, preferably per daily intake or dosage for one human, particularly one adult, and more preferably such that termenol A is 80 μg or more and termenol B is 20 μg or more. According to these embodiments, an effect of suppressing cancer cell proliferation, an anti-cancer effect, an effect of suppressing the canceration of normal cells, an effect of suppressing cancer onset, or an effect of inducing cancer cell death can be effectively obtained. Here, the "daily intake or dosage" refers to the amount of the composition of the present invention, which is typically 0.1 g to 500 g, in the case of ingestion or administration orally or nasally, preferably orally. The active ingredient used in the present invention, or a composition or medicine containing the same, may be continuously ingested or administered, or may be ingested or administered as needed.

[0037] The active ingredient used in the present invention, or the composition or medicament containing the same, may be the active ingredient itself, or may contain the active ingredient and at least one other ingredient. When the active ingredient used in the present invention, or the composition or medicament containing the same, contains the active ingredient and at least one other ingredient, it may be a composition obtained by mixing the active ingredient and at least one other ingredient, or may be a composition obtained by formulating the active ingredient and at least one other ingredient by appropriate means, or may be a composition obtained by further mixing the formulated composition of the active ingredient and at least one other ingredient with other ingredients.

[0038] The shape of the active ingredient used in the present invention, or the composition or medicament containing the same, is not particularly limited, and may be any shape such as liquid, fluid, gel, semi-solid, or solid.

[0039] The at least one other ingredient that the active ingredient used in the present invention, or the composition or medicament containing the same, may contain is not particularly limited, but is preferably an ingredient that is acceptable in the final forms such as pharmaceuticals, foods and drinks, feeds, food additives, feed additives, etc., and ingredients that can be orally ingested can be exemplified.

[0040] Examples of such other ingredients include sweeteners, acidulants, vitamins, minerals, thickeners, emulsifiers, antioxidants, water, etc. Further, if necessary, dyes, flavors, preservatives, antiseptics, fungicides, further physiologically active substances, etc. may be added.

[0041] Examples of sweeteners include monosaccharides and disaccharides such as glucose, fructose, sucrose, lactose, maltose, palatinose, trehalose, xylose, isomerized sugars (glucose-fructose liquid sugar, fructose-glucose liquid sugar, sugar mixed isomerized sugar, etc.), sugar alcohols (erythritol, xylitol, lactitol, palatinit, sorbitol, reduced starch syrup, etc.), honey, high-intensity sweeteners (sucralose, acesulfame potassium, thaumatin, stevia, aspartame, etc.).

[0042] Examples of acidulants include citric acid, malic acid, gluconic acid, tartaric acid, lactic acid, phosphoric acid, or salts thereof, and one or more of these can be used.

[0043] Examples of vitamins include vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin E, niacin, inositol, and the like.

[0044] Examples of minerals include calcium, magnesium, zinc, iron, and the like.

[0045] Examples of thickeners include carrageenan, gellan gum, xanthan gum, gum arabic, tamarind gum, guar gum, locust bean gum, karaya gum, agar, gelatin, pectin, soybean polysaccharides, carboxymethyl cellulose (CMC), and the like.

[0046] Examples of emulsifiers include glycerin fatty acid esters, sucrose fatty acid esters, sorbitan fatty acid esters, lecithin, plant sterols, saponins, and the like.

[0047] Examples of antioxidants include vitamin C, tocopherol (vitamin E), enzyme-treated rutin, catechin, and the like.

[0048] The above other components can each be appropriately formulated in an amount within the range usually employed by those skilled in the art for compositions such as food and beverages, pharmaceuticals, etc.

[0049] The composition or pharmaceutical form obtained by formulating the active ingredient used in the present invention and at least one other component by appropriate means may be in the form of a solid composition such as powder, granule, capsule, tablet (including coated tablets such as sugar-coated tablets or multilayer tablets, orally disintegrating tablets, chewable tablets, etc.), or may be in the form of a liquid composition such as a solution.

Examples

[0050] 1. Evaluation of anticancer effect Tumeronol A and Tumeronol B (both commercially available from Nagara Science Co., Ltd.) were dissolved in dimethyl sulfoxide and used in the following tests.

[0051] HT-29 cells, a human colorectal cancer cell line, were suspended in RPMI 1640 medium (containing 10% FBS) and seeded in a 96-well microplate at a cell density of 3.0×10 3 cells per well, and cultured for 24 hours under the conditions of 37°C and 5% CO2. The HT-29 cells cultured in the 96-well plate were then cultured for 72 hours in RPMI 1640 medium (containing 2.5% FBS) containing either Tumeronol A or Tumeronol B at amounts of 12.5 μM, 25 μM, 50 μM, or 100 μM. Two hours before the end of the culture, the WST-1 reagent was added, and the absorbance (cell metabolic activity) was measured with a plate reader two hours later. The metabolic activity of HT-29 cells cultured in the same procedure except using RPMI 1640 medium without the specimens (Tumeronol A, Tumeronol B) was taken as 100%, and the change rate of the metabolic activity of HT-29 cells cultured in RPMI 1640 medium containing each concentration of the specimens was determined. Here, the cell metabolic activity means the cell proliferation activity and the life-sustaining activity including excessive activation.

[0052] The results for Tumeronol A are shown in Figure 1, and the results for Tumeronol B are shown in Figure 2, respectively. Figure 1 shows that when HT-29 cells were treated with Tumeronol A, the cell metabolic activity significantly decreased in a dose-dependent manner. Similarly, Figure 2 shows that when HT-29 cells were treated with Tumeronol B, the cell metabolic activity significantly decreased in a dose-dependent manner. From these results, it was shown that both Tumeronol A and Tumeronol B suppress the metabolic activity of colorectal cancer cells. Here, the suppression of the cancer cell metabolic activity means the suppression of cancer cell proliferation, the suppression of carcinogenesis, and the induction of cancer cell death.

[0053] All publications, patents, and patent applications cited in this specification are hereby incorporated by reference in their entirety.

Claims

1. A composition for inhibiting the growth of colorectal cancer cells, containing ternomol A as an active ingredient (excluding compositions containing turmeric extract).

2. A composition for anti-cancer against colorectal cancer, containing ternomol A as an active ingredient (excluding compositions containing turmeric extract).

3. A composition for inducing colorectal cancer cell death, containing ternomol A as an active ingredient (excluding compositions containing turmeric extract).

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