Tumor promotion inhibitors

Abstract

To provide a novel oncogenic promotion inhibitor.SOLUTION: Provided is an oncogenic promotion inhibitor containing Polygala tenuifolia as an active ingredient.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a tumor promotion inhibitor. [Background technology]

[0002] The number of cancer patients is increasing year by year, and cancer is now the leading cause of death in Japan. In 2017, approximately 860,000 new cases of cancer were diagnosed, and approximately 370,000 cases died from cancer. Cancer is treated by chemotherapy, surgical procedures, radiation therapy, etc., but the therapeutic effects are not always satisfactory, and this can lead to a decrease in the quality of life of patients. It is also said that cancer cannot be completely prevented from recurring after treatment. Therefore, as with other diseases, a preventive medical perspective is required, and methods to prevent carcinogenesis, including cancer recurrence, are attracting attention.

[0003] Generally, cancer prevention methods include lifestyle changes such as quitting smoking and reviewing dietary habits, and environmentally friendly measures such as dealing with stress, but as a more proactive measure, the development of substances that are effective in cancer prevention is desired. Cancer is thought to begin when the genes of normal cells are damaged (initiation), and then the characteristics change and unregulated proliferation is added (promotion). It is thought that inhibiting these processes will lead to cancer prevention.

[0004] Thus, various preventive agents that inhibit or suppress the initiation activity and / or promotion activity of carcinogens have been proposed (for example, Patent Documents 1 to 3). Patent Documents 1 to 3 contain, as active ingredients, Acanthus arguta fruit juice or a highly polar organic solvent extract of Acanthus arguta fruit juice, a polymer composition derived from tea leaves, or a compound extracted from red yeast rice.

[0005] Recently, the Bhas 42 cell transformation assay has been published as a test method capable of detecting substances that affect carcinogenesis promotion in vitro with high accuracy (e.g., Non-Patent Document 1). The Bhas 42 cells used in this assay are a cell line established by introducing the v-Ha-ras oncogene into BALB / c 3T3 cells (whole mouse fetuses). [Prior art documents] [Patent documents]

[0006] [Patent Document 1] JP 2013-136556 A [Patent Document 2] JP 2013-95694 A [Patent Document 3] JP 2008-56618 A [Non-patent literature]

[0007] [Non-Patent Document 1] GUIDANCE DOCUMENT ON THE IN VITRO BHAS 42 CELL TRANSFORMATION ASSAY, Series on Testing & Assessment No. 231 (2016) Summary of the Invention [Problem to be solved by the invention]

[0008] An object of the present invention is to provide a novel tumor promotion inhibitor. [Means for solving the problem]

[0009] In order to achieve the above object, the present inventors have conducted extensive research and found that Unshiu Zhi has the effect of suppressing cancer promotion. That is, the present invention is a cancer promotion inhibitor containing Unshiu Zhi as an active ingredient. Effect of the Invention

[0010] According to the present invention, a novel tumor promotion inhibitor can be provided. [Brief description of the drawings]

[0011] [Figure 1] FIG. 1 shows the effect of a herbal medicine (Noukatsusei) on the increase in focus number caused by the addition of a tumor promoter (TPA). [Diagram 2] FIG. 1 shows the effect of Enshi on the increase in focus number caused by the addition of a tumor promoter (TPA). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] The cancer promotion inhibitor of the present invention contains Polygalae Radix as an active ingredient. Polygalae Radix is ​​the root or root bark of Polygala tenuifolia Willdenow (Polygalaceae) (17th Revised Japanese Pharmacopoeia). Representative pharmacological actions of Polygalae Radix have been known so far as expectorant, antitussive, sedative, and memory learning improvement actions. The present inventors have found that Polygalae Radix has an action of suppressing cancer promotion, specifically, an action of suppressing the change in the characteristics of tumor cells caused by tumor promoters and the unregulated proliferation of tumor cells whose characteristics have been changed.

[0013] As the polysaccharide, for example, a commercially available product, Onji Dry Extract (Alps Yakuhin Co., Ltd.), can be used. Alternatively, a dried extract prepared by a conventional method from the roots of Polygala tenuifolia may be used. The dried extract can be prepared by obtaining an extract from the roots of Polygala tenuifolia by a known method, concentrating, sterilizing, and drying. Examples of the dried extract include an aqueous dried extract and an ethanol extract.

[0014] The carcinogenesis promotion inhibitor of the present invention may contain saffron or red ginseng as an active ingredient in addition to Crocus sativus Linne. Saffron is the stigma and upper part of the style of Crocus sativus Linne, and its representative pharmacological actions have been known to be sedative, analgesic, and menstrual. Red ginseng is the root of Panax ginseng CA Meyer, which is steamed and then dried, and its representative pharmacological actions have been known to be nourishing and strengthening, improving blood flow, lowering blood sugar, and anti-stress. When such ingredients are contained, the carcinogenesis promotion inhibitory action is further enhanced.

[0015] Alternatively, the carcinogenesis promotion inhibitor of the present invention may contain both saffron and red ginseng in addition to Radix Candida. Radix Candida, saffron and red ginseng are contained in a herbal medicine preparation (Noukatsusei) together with Antelope horn and Agarwood. This herbal medicine preparation is commercially available as an OTC drug, and has the efficacy of nutritional tonic (weak constitution, physical fatigue, during and after illness, weak stomach and intestines, loss of appetite, poor complexion, poor circulation, and growth period). The present inventors have discovered that a herbal medicine preparation (Noukatsusei) containing Solanum Root, Saffron and Red Ginseng has the effect of suppressing carcinogenesis promotion.

[0016] In the tumor promotion inhibitor of the present invention, Cornus officinalis, Saffron and Red Ginseng can be used as raw herbal medicines, but it is preferable to use them as extracts extracted from the raw herbal medicines or as pulverized materials (powder) obtained by pulverizing the raw herbal medicines. For example, a dried water extract of Red Ginseng can be used. The methods of extraction and pulverization are not particularly limited as long as they are methods used in the manufacture of medicines and foods, and any method can be used.

[0017] For example, each pulverized raw material can be extracted with hot water in an amount 5 to 30 times, preferably 10 to 20 times, its mass, and the resulting extract can be concentrated and dried for use. The raw material can be pulverized using known means such as an impact mill or a jet mill. For concentration and drying, known means such as reduced pressure evaporation, spray drying, and freeze drying can be used.

[0018] The carcinogenesis promotion inhibitor of the present invention can be prepared as a preparation containing, for example, 0.03-30 mg of dried onji extract, 0.1-100 mg of saffron powder, and 0.3-300 mg of dried red ginseng extract as active ingredients per 1 kg of human body weight per day. In this case, the preparation can contain 0.1-100 mg of antelope horn powder and 0.01-10 mg of agarwood as ingredients other than the active ingredients. Furthermore, the preparation can contain pearl, corn starch, and flavoring (ryunou) as additives. These ingredients can also be encapsulated with gelatin.

[0019] The carcinogenesis promotion inhibitor of the present invention can be prepared by a method known to those skilled in the art together with an appropriate excipient depending on the administration method. Examples of the administration method include oral administration, topical administration, rectal administration (suppository), and parenteral administration such as eye drops. Among them, oral administration and topical administration are preferred. When administered orally, the above-mentioned daily amount can be administered all at once or in several divided doses. Administration may be performed before, after, or between meals, and the administration period is not particularly limited.

[0020] The carcinogenesis promotion inhibitor of the present invention can be in any dosage form for oral or parenteral administration. Examples include granules, fine granules, tablets, powders, capsules, chewable agents, liquids, and suspensions. These can be formulated by conventional methods. Examples of the form for injection include direct intravenous injection and drip administration. If necessary, carriers such as lactose, glucose, D-mannitol, starch, crystalline cellulose, calcium carbonate, kaolin, and gelatin, and conventional additives such as solvents, solubilizers, and isotonicity agents may be appropriately blended.

[0021] The topical preparation containing the carcinogenesis promotion inhibitor of the present invention is of a percutaneous absorption type. If necessary, known additives and the like can be mixed to prepare topical preparations by conventional methods. Specific examples of topical preparations include creams, liquids, lotions, emulsions, tinctures, ointments, aqueous gels, oily gels, aerosols, powders, shampoos, and soaps. The daily dose of such topical preparations can be appropriately set according to the symptoms, purpose, age, and administration method of the subject to be administered.

[0022] The cancer promotion inhibitor of the present invention can be contained in food. The food containing the cancer promotion inhibitor of the present invention can be in the form of a general food or drink. For example, it can be used as it is or can be made into a drink, such as a soft drink or powdered drink, by adding an appropriate flavor to it. Specifically, it can be added in an appropriate amount to juice, milk, confectionery, jelly, etc. and consumed.

[0023] Foods containing the carcinogenesis promotion inhibitor of the present invention can be provided as health functional foods, such as foods for specified health uses or foods with nutrient function claims, for the prevention of cancer.

[0024] Furthermore, the food containing the carcinogenesis promotion inhibitor of the present invention can be used as a concentrated liquid diet or a food supplement. When used as a food supplement, it can be prepared in the form of, for example, tablets, capsules, powders, granules, suspensions, chewable agents, syrups, etc. Food supplements refer to those that are taken for the purpose of supplementing nutrition other than those taken as food, and include nutritional supplements and dietary supplements. Foods can be processed and produced by mixing the tumor promotion inhibitor of the present invention with general food ingredients in a conventional manner.

[0025] When the cancer promotion inhibitor of the present invention is contained in a food, an appropriate amount of the food may be ingested so that a predetermined amount of the cancer promotion inhibitor is ingested. The amount of food to be ingested can be appropriately selected depending on the content of the cancer promotion inhibitor in the food.

[0026] Examples of nutritional supplements or functional foods include processed forms such as liquid foods, semi-digested nutritional foods, elemental nutritional foods, drinks, capsules, and enteral nutrients that contain sugars, fats, trace elements, vitamins, emulsifiers, and flavors. The above-mentioned various foods, such as sports drinks and nutritional drinks, can further contain nutritional additives such as amino acids, vitamins, and minerals, as well as sweeteners, spices, flavors, and colorings, in order to improve nutritional balance and flavor. Furthermore, tocopherol, L-ascorbic acid, BHA, rosemary extract, and the like can be used as antioxidants that are usually added to foods in the usual manner.

[0027] The carcinogenesis promotion inhibitor of the present invention can be added to livestock, poultry, and pet feed to prevent cancer in these animals. As for the form, it can be added to dry dog ​​food, dry cat food, wet dog food, wet cat food, semi-moist dog food, chicken feed, and livestock feed for cows, pigs, etc.

[0028] Furthermore, the carcinogenesis promotion inhibitor of the present invention can also be used appropriately in animals other than humans, for example, livestock mammals such as cows, horses, pigs, and sheep, poultry such as chickens, quails, and ostriches, and pets such as reptiles, birds, and small mammals.

[0029] The inhibitory effect of the tumor promotion inhibitor of the present invention on tumor promotion is the inhibitory effect on transformation, and can be confirmed with reference to the Bhas 42 cell transformation assay. EXAMPLES

[0030] The tumor promotion inhibitor according to the present invention will be specifically described below, but the present invention is not limited thereto.

[0031] (Test Drug 1) A herbal preparation (Noukatsusei) (0.313 mg / mL, 1.25 mg / mL, 5 mg / mL) was prepared as test drug 1. The herbal preparation (Noukatsusei) was subjected to ultrasonic extraction with 10% dimethyl sulfoxide for 30 minutes, and the supernatant obtained after centrifugation (1000 rpm for 3 minutes) was sterilized by filtration. The final solvent concentration was 1%.

[0032] The herbal medicine preparation (Neng Kao Jing) contains 30mg of dried extract of Enzhi, 90mg of powdered saffron, 330mg of dried extract of red ginseng, 100mg of powdered antelope horn, and 10mg of agarwood in a daily dose (4 capsules). In addition, it contains pearl, corn starch, and flavoring (Ryuno) as additives, and the mixture containing these is encapsulated in gelatin.

[0033] (Test Drug 2) Test drug 2 was prepared as 0.00390mg / mL, 0.0130mg / mL, 0.0390mg / mL, and 0.130mg / mL. 0.00390mg / mL and 0.130mg / mL. 0.00390mg / mL and 0.130mg / mL. 0.00390mg / mL and 0.130mg / mL. 0.00390mg / mL and 0.130mg / mL were prepared ...

[0034] [Cancer promotion inhibition test] The tumor promotion inhibitory effect of the test drug was evaluated using a tumor promoter with reference to the Bhas 42 cell transformation test method (Non-Patent Document 1). First, Bhas 42 cells (1.4 × 10 4 The cells were seeded in a 35 mm dish and culture was started (day 0). On days 4, 7, and 11 after the start of culture, the medium was replaced with 10% FBS-containing DMEM:F12 medium containing the specified concentrations of the test drug.

[0035] In addition to the prescribed concentrations of the test drugs, 50ng / mL of 12-O-Tetradecanoylphorbol 13-acetate (TPA) was added to the 10% FBS-containing DMEM:F12 medium. TPA is a potent tumor promoter that is well known to activate signaling pathways downstream of protein kinase C (PKC). After changing the medium on the 14th day, the cells were cultured until the 21st day and then fixed with methanol. The cells were stained with 5% Giemsa stain and observed under a microscope to count the foci (transformation foci) to evaluate the inhibitory effect of the test drug on the transformation promotion by TPA.

[0036] (Example 1: Carcinogenesis promotion inhibitor containing herbal medicine (Noukatsusei)) Figure 1 shows the effect of herbal medicines on tumor promotion in Bhas 42 cells. In Figure 1, data are shown as mean ± standard error (mean ± SE). Multiple comparison test (Dunnett's method) was used to analyze significant differences from the control group without the addition of herbal medicines. ** indicates p<0.01. From the results in Figure 1, it was confirmed that herbal preparations (Nokatsusei) at 0.313 mg / mL or more suppressed the increase in focus number caused by the addition of TPA, and in particular, herbal preparations (Nokatsusei) at 1.25 mg / mL or more significantly suppressed the increase in focus number. Furthermore, when the herbal preparation (Nokatsusei) was contained at 5 mg / mL, the number of foci was reduced compared to the normal group. This suggests that the effect of the herbal preparation (Nokatsusei) on transformation in Bhas 42 cells does not specifically inhibit the promoting effect of TPA, and further suggests that this herbal preparation has the effect of broadly suppressing the expression of transformation.

[0037] (Example 2: Tumor promotion inhibitor containing fermented soybean) Figure 2 shows the effect of E. coli on tumor promotion in Bhas 42 cells. In Figure 2, the data are shown as mean ± standard error (mean ± SE). A multiple comparison test (Dunnett's method) was used to analyze the significant difference from the control group without E. coli. ** indicates p<0.01. From the results in Figure 2, it was confirmed that 0.00390mg / mL or more of fermented soybean oil suppressed the increase in the number of foci caused by the addition of TPA, and in particular, 0.0130mg / mL or more of fermented soybean oil significantly suppressed the increase in the number of foci caused by the addition of TPA. Furthermore, when 0.0390mg / mL or more of fermented soybean oil was contained, the number of foci was reduced compared to the normal group. This suggests that the effect of fermented soybean oil on the transformation of Bhas 42 cells does not specifically inhibit the promoting effect of TPA, and furthermore, that fermented soybean oil has the effect of broadly suppressing the expression of transformation.

Claims

[Claim 1] A carcinogenic promotion inhibitor containing saffron, saffron, and red ginseng as active ingredients.

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