JP5288397B2 - Anticancer agents derived from natural ingredients that can be taken orally - Google Patents

Description

  The present invention relates to an anticancer agent derived from a natural ingredient that can be taken orally.

  Cancer is the leading cause of death in Japan, and in today's aging society, where life expectancy has been extended, the number of cancer deaths among the elderly has been increasing due to the lack of effective anticancer drugs. Is traced. Cancer develops in all organs as the primary focus, and further, the cancer spreads in the metastatic focus, and the cancer spreads throughout the body. Therapies for cancer include surgical therapy, radiation therapy, and chemotherapy such as administration of anticancer drugs. The effects of anticancer drugs include cancer cell growth inhibition and primary It is essential to prevent the spread of cancer cells in the nest and metastasis, and drugs such as alkylating agents, antimetabolites, anticancer antibiotics, plant alkaloids are used clinically. However, these drugs kill tumor cells and also act on normal cells. Therefore, due to the low specificity of the action, the function of organs associated with normal cell injury and the body formation by suppressing hematopoiesis in the bone marrow It has often been reported to have side effects such as weakness. Many cancer drugs show side effects that are more serious than their therapeutic effects, and no absolute drugs have been developed. Therefore, the development of new drugs with few side effects is desired.

  On the other hand, pepper is a solanaceous plant and is used all over the world as a food, a spice, and a pharmaceutical raw material. Its main pungent component capsaicin is a kind of vanillyl fatty acid amide in which vanillyl alcohol and branched unsaturated fatty acid are amide-bonded, promoting appetite, promoting energy metabolism, bactericidal, antiseptic, increasing immunity, Various effects such as fat burning are known. In addition to these effects, anticancer effects have also been reported (see Non-Patent Document 1 and Non-Patent Document 2). However, the use of capsaicin is limited due to the strong pungency, irritation, or inflammation-inducing action of capsaicin.

  On the other hand, from the hot pepper varieties “CH-19” obtained in Thailand, a new hot pepper cultivar “CH-19 sweet” without selection is selected and fixed, and it is reported that it contains a large amount of capsaicinoid-like substances ( Non-Patent Document 3), separation and purification and structural analysis of such capsaicinoid-like substances were attempted, and capsiate (4-hydroxy-3-methoxy-benzyl-8-methyl-6- (E) -nonanoate) and dihydrocapsiate (4 -Hydroxy-3-methoxy-benzyl-8-methyl-6-nonanoate) was identified (see Patent Documents 1 and 2). Thereafter, an analgesic (see Patent Document 3) containing a capsiate, a composition for improving endurance (see Patent Document 4), an anti-pruritic composition (see Patent Document 5), a diabetic blood sugar level-lowering composition (Patent Document 6) Etc.) have been proposed.

  In addition, a cancer cell growth inhibitor containing capsorubin or a fatty acid ester thereof as an active ingredient based on the knowledge that capsorubin or a fatty acid ester thereof, which is a kind of carotenoid contained in red pepper, has the activity of suppressing the growth of lung cancer cells, It has been proposed (see Patent Document 7).

  Furthermore, based on the knowledge that the vanillylamine structure of capsaicin, a pungent component of capsicum, binds to the vanilloid receptor, which is an in vivo receptor necessary for the expression of the physiological action of capsaicin, and to eliminate side effects such as capsicin's pungent and irritating properties, An antitumor pharmaceutical composition based on vanillyl fatty acid amide synthesized by replacing the 8-methyl-6-nonene residue of capsaicin with an acyl group having 14 or more carbon atoms has been proposed (Patent Document 8). reference).

Japanese Patent Laid-Open No. 11-246478 JP 2003-18974 A JP 2001-158738 A JP 2002-114676 A JP 2003-321361 A JP 2003-342172 A JP 2004-43418 A JP 2004-182673 A D.J.Morre et.al., Proc. Natl. Acad. Sci., 92, 1831-1835 (1995) K. Takahata et.al, Life Science, 64, PL 165-171 (1999) Yazawa et al., J.A. Japan Soc. Hort. Sci., 58: 601-607 (1989)

  As mentioned above, capsaicin is accompanied by a stimulus such as causing intense burning sensation, and its use is limited due to its strong pungent taste. . Moreover, the cancer inhibitory effect of capsorbin or a fatty acid ester thereof, which is a carotenoid, has only been confirmed in lung cancer cells, and its systemic effects and side effects are unknown.

  The problem of the present invention is that it is derived from food, does not cause side effects such as gastrointestinal disorders, can be continuously consumed orally without limiting the amount of use, etc., and has no side effects such as physical weakness. It is another object of the present invention to provide an anticancer agent or the like that has a remarkable effect as a systemic powerful anticancer agent and that can prevent or treat cancer.

  The present inventors have found that capsiate present in capsicum has an anticancer preventive and therapeutic action. That is, the present invention suppresses the growth of cancer cells and effectively prevents metastasis and tissue destruction in cancer model mice by ingesting natural component capsiate purified and isolated from non-spicy pepper. It was confirmed that it shows the efficacy of a powerful anticancer drug throughout the body. Moreover, the effect was equal to or better than that of a compound developed as a pharmaceutical, significantly reduced body weight loss due to cancer, and could be continuously administered orally. The present invention has been completed based on these findings.

That is, the present invention provides [1] an anticancer agent characterized by comprising a compound represented by formula (I) or the compound-containing composition as a single active ingredient , wherein the cancer is metastatic. Anticancer drug that is malignant melanoma

(Wherein n represents an integer of 1 to 10 and m represents 0 or 1) and [2] the compound represented by the above formula (I) is capsiate, dihydrocapsiate, or nordihydrocapsiate. and wherein about the anticancer agent according to [1].

  According to the present invention, by using vanillyl fatty acid such as capsiate as an active ingredient, it has a novel effect of capsiate with low side effects and high cancer therapeutic effect, and can be taken orally daily An anti-cancer drug that has a prominent effect that can prevent and treat various cancers, and a food or food material that is labeled as being used for the prevention or treatment of cancer be able to.

  The anticancer agent of the present invention includes a compound represented by formula (I)

(In the formula, n represents an integer of 1 to 10, and m represents 0 or 1), or any compound containing the compound-containing composition as an active ingredient is not particularly limited. The food or food material for cancer prevention / treatment of the present invention is particularly limited as long as it contains the compound represented by the above formula (I) or the compound-containing composition as an active ingredient. Here, prevention / treatment of cancer means that cancer can be prevented or symptoms can be improved.

  In the compound represented by the formula (I), when m = 1, n = 1 to 8 is preferable, n = 2 to 6 is more preferable, n = 3 to 5 is particularly preferable, and n = 4 is most preferable. Preferably, specifically, a capsiate represented by the following formula (II) can be suitably exemplified, and the double bond of the branched unsaturated fatty acid moiety is trans-form 4-hydroxy-3-methoxy-benzyl -8-methyl-6- (E) -nonenoate can be particularly preferably exemplified.

  In the compound represented by the above formula (I), when m = 0, n = 2 to 9 is preferable, n = 3 to 8 is more preferable, n = 4 to 7 is particularly preferable, and n = 5 among them. -6 are most preferable, specifically, a dihydrocapsiate represented by the following formula (III) or a nordihydrocapsiate represented by the following formula (IV) is preferably exemplified. Can do.

  As a method for producing the compound represented by the above formula (I) or the compound-containing composition, a method for separating and extracting vanillyl fatty acid ester from a plant, a branch appropriately selected from vanillyl alcohol based on the above formula (I) There is no particular limitation including known methods such as a method of chemically synthesizing from an unsaturated fatty acid by a known esterification reaction. And the compound of the present invention represented by the formula (II) comprises 8-methyl-6-nonenoic acid, preferably 8-methyl-trans-6-nonenoic acid and vanillyl alcohol. It can be synthesized as a starting material. The plant to be extracted is not particularly limited as long as it is a plant containing such a compound, but a plant belonging to the genus Capsicum is preferable, and a variety of genus Capsicum having a strong sweetness is more preferably used. CH-19 sweet, Fushimi sweet long, paprika, bell pepper, etc. can be illustrated. Among them, it is preferable to use CH-19 sweet, which has been confirmed to be a variety containing a large amount of capsiate, but a variety containing a large amount of capsiate produced by crossing with two or more varieties containing capsiate. May be used. The compound-containing composition represented by the formula (I) is an artificial content of the compound represented by the formula (I), such as various compositions in which the compound represented by the formula (I) is blended. Refers to a mixture of compounds represented by the formula (I) in which is increased.

  Cancers for which the anticancer agent of the present invention is effective include malignant melanoma, skin cancer, lung cancer, tracheal and bronchial cancer, oral epithelial cancer, esophageal cancer, stomach cancer, colon cancer, rectum Cancer in which epithelial cells such as cancer, colon cancer, liver and intrahepatic bile duct cancer, kidney cancer, pancreatic cancer, prostate cancer, breast cancer, uterine cancer, ovarian cancer, brain tumor, etc. have become malignant Tumors, myomas, osteosarcomas, Ewing sarcomas, etc. cells that constitute the supporting tissue are derived from hematopoietic cells such as cancers or tumors with leukemia, malignant lymphoma, myeloma, Burkitt lymphoma, etc. Malignant melanoma can be cited as the most reliable example in that it can prevent blood circulation and lymphatic invasion and metastasis to organs other than the primary lesion. .

  When the compound represented by the above formula (I) or the compound-containing composition is used as a medicine for preventing or treating cancer, a pharmaceutically acceptable normal carrier, binder, stabilizer, Various preparation compounding ingredients such as excipients, solubilizers, solubilizers, and isotonic agents can be added. Examples of the dosage form include suspensions, powders, granules, capsules, and the like. Depending on the form, for example, intravenous, subcutaneous, intramuscular, intraperitoneal injection, etc. In addition, it may be administered orally and via the nasopharynx, but the compound represented by the above formula (I) is different from capsaicin and, as mentioned above, hardly gives any irritation to the human skin and internal organs. Oral administration is most preferable in the present invention in that it can be taken orally and there is almost no quantitative limitation. The dose can be appropriately selected depending on various administration conditions such as prevention or treatment, administration method, severity, patient age, etc. Can be selected according to the case from a wide range, but in the case of an adult, preferably 100 mg to 2 g per day can be exemplified.

  Moreover, since the compound represented by the above formula (I) is contained in natural food such as pepper and does not irritate the human body, it is determined that there is no need for side effects after administration. In the mice administered with the same compound in the examples, no particularly significant side effects were observed either externally or anatomically.

  Moreover, it can be set as the food or food material for cancer prevention by adding the compound represented by the said formula (I), or this compound containing composition to food-drinks. As an embodiment thereof, a food or food material, which is characterized by the addition of a compound represented by formula (I) and labeled as being used for the prevention / treatment of cancer; A food or food material characterized by the addition of a compound-containing composition represented by I) and labeled as being used for cancer prevention / treatment; represented by formula (I) A method of using a food or food material to which a compound to be added is added as a food or food material for cancer prevention / treatment; a food or food material to which a compound-containing composition represented by formula (I) is added, Method for using as a food or food material for cancer prevention / treatment; Method for using a compound represented by formula (I) as a food or food material combination for cancer prevention / treatment; A compound-containing composition represented by a food for cancer prevention / treatment Is a method for using as a food ingredient compounding method; a method for producing a food or food material for cancer prevention or treatment characterized by adding a compound represented by formula (I) to a food or food material; Examples thereof include a method for producing a food or food material for cancer prevention / treatment characterized by adding the compound-containing composition represented by I) to the food or food material.

  Examples of the food or food material for cancer prevention / treatment of the present invention include yogurt, drink yogurt, juice, milk, soy milk, liquor, coffee, tea, sencha, oolong tea, sports drinks, Baked confectionery such as cookies, bread, cakes, jelly, rice crackers, Japanese confectionery such as sheep crab, bread and confectionery such as frozen confectionery, chewing gum, noodles such as udon and soba, fish paste products such as kamaboko, ham and fish sausage , Miso, soy sauce, dressing, mayonnaise, sweeteners, dairy products such as cheese, butter, tofu, konjac, other boiled fish, dumplings, croquettes, salads it can. The term “for cancer prevention / treatment” refers to a case where a food or food material packaging container or instructions indicate that it is effective for the prevention or treatment of cancer.

  EXAMPLES Hereinafter, although an Example demonstrates this invention more concretely, the technical scope of this invention is not limited to these illustrations.

[Metastatic Melanoma Cell B16 Cell Metastasis Experiment]
Established as a metastasis experiment model selected from mouse melanoma B16 cells, metastasis experiments were conducted using malignant melanoma B16 cells, which can easily metastasize to lymphatic or hematogenous and nodular lesions can occur in any part of the whole body. went. M16 melanoma cell B16 cells (RCB1283, RIKEN CELL BANK) in the logarithmic growth phase were cultured and then suspended in phosphate buffered saline (PBS). The 6-week-old male C57BL / 6 mouse (purchased from Japan SLC Co., Ltd.) was transferred to the malignant melanoma cell B16 cells (2 × 10 ⁵ cells) via the tail vein to obtain a cancer disease model mouse. Once a day from the day of transfer, 5 mg of Capsiate (Ajinomoto Co., Inc.) per kg of mouse body weight was forcibly orally administered to the cancer disease model mice using an oral sonde. Lung, liver, kidney, lymph node and femur tissues were excised 18 days after the tail vein transfer of the malignant melanoma cells. The lung, liver, kidney, and lymph node were each fixed in a 10% formalin solution, and the number of cancer nodules was counted for each tissue under a microscope. A control cancer disease model mouse was administered with physiological saline instead of capsiate.

In addition to the above-mentioned capsiate-administered cancer disease model mouse (B16 +) and the above-mentioned non-capsiate-administered control cancer disease model mouse (B16-), capsaiate was applied to normal mice that did not transfer the malignant melanoma cell B16 cells to the tail vein. For four types of mice, one administered with (normally +) and one not administered with capsiate (usually-), the excised femur was fixed with 70% ethanol, and then two high and low X The bone density was measured by the DEXA method (Dual Energy X-ray Absorptiometry) in which the bone density was calculated from the difference in the transmittance. In addition, as an evaluation of the general condition of the four groups of mice, the body weight was compared on the 18th day after the transfer of the tail vein before the extraction of each tissue. For the four types of mice, it was confirmed that the average femur density (31.0 mg / cm ² ) and the average body weight (23.1 g) were almost the same before the experiment.

[result]
FIG. 1 shows a photograph of lung cancer nodules and femurs and the number of cancer nodules extracted from the above-mentioned capsiate-administered cancer disease model mice and the above-mentioned non-capsiate-administered control cancer disease model mice. In the control cancer disease model mice not treated with capsiate, the formation of marked cancer nodules of cancer cells was confirmed in the lung, liver, kidney and lymph nodes. The formation of nodules was suppressed. In addition, regarding cancer formed in bone, formation of cancer nodules and bone destruction were observed in the femur extracted from the control cancer disease model mice not treated with capsiate. Then, the formation of cancer nodules and bone destruction were suppressed.

  FIG. 2 shows the number of cancer nodules in the lung, liver, kidney, and lymph nodes excised from the two types of mice, the capsiate-administered cancer disease model mouse and the control cancer disease model mouse not administered with capsiate. Significant differences were determined using t-test, and statistically significant if P value was 0.05 or less (*) or 0.001 or less (**). Capsiate significantly suppressed the formation of cancer nodules in the lung, liver, kidney and lymph nodes.

  Fig. 4 shows femoral bone density of capsiate-administered cancer disease model mice (B16 +), capsiate-untreated control cancer disease model mice (B16-), capsiate-administered normal mice (usually +), and capsiate-untreated normal mice (usually-). It is shown in 2. The capsiate-administered cancer disease model mice had significantly lower femur density than normal mice (usually +) and normal mice (usually-) (p <0.001). Significantly higher compared to mice (p <0.05).

  Fig. 2 shows the body weights of capsiate-administered cancer disease model mice (B16 +), capsiate-untreated control cancer disease model mice (B16-), capsiate-administered normal mice (usually +), and capsiate-untreated normal mice (usually-). Show. The weight of the capsiate-administered cancer disease model mice was significantly lower (p <0.001) compared to normal mice (usually +) and normal mice (usually-). Were significantly higher (p <0.05).

  In cancer model mice, metastasis from primary tumor to lung, liver, kidney, lymph node, and femur and growth of cancer were confirmed, but capsiate suppresses both cancer metastasis and growth. It was confirmed. Moreover, although the weight loss by the cancer invasion to each organ was observed in the said cancer disease model mouse, it is thought that the weight loss was suppressed by capsiate administration.

  Based on the above results, capsiate has systemic anti-cancer effects when administered orally, avoiding weight loss as a side effect due to the use of conventional anti-cancer agents, and is useful as a cancer therapeutic agent It was confirmed.

It is a figure which shows the influence of a capsiate by the nodule number of cancer by the tail vein transfer of B16 cell. Photographs of lung cancer nodules and femur cancer nodules removed from capsiate-untreated control cancer disease model mice, lung cancer nodules and femoral cancer nodules removed from capsiate-administered cancer disease model mice Each is shown. It is a figure which shows numerically the influence of the capsiate by the number of nodules of cancer by the tail vein transfer of B16 cell. The number of lung cancer nodules, liver cancer nodules, kidney cancer nodules, and lymph node cancer nodules removed from capsiate-untreated control cancer disease model mice and capsiate-treated cancer disease model mice Show. The capsiate-administered cancer disease model mouse (B16 +), the capsiate non-administration control cancer disease model mouse (B16-), the capsiate-administered normal mouse (normal +), and the capsiate-unadministered normal mouse (normal-) Indicates body weight.

Claims (2)

An anticancer agent comprising the compound represented by formula (I) or the compound-containing composition as a single active ingredient , wherein the cancer is metastatic malignant melanoma Agent ;


(In the formula, n represents an integer of 1 to 10, and m represents 0 or 1). The anticancer agent according to claim 1, wherein the compound represented by the formula (I) is capsiate, dihydrocapsiate, or nordihydrocapsiate.