JP5175442B2 - Yacon-derived anticancer agent - Google Patents
Yacon-derived anticancer agent Download PDFInfo
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- JP5175442B2 JP5175442B2 JP2006057997A JP2006057997A JP5175442B2 JP 5175442 B2 JP5175442 B2 JP 5175442B2 JP 2006057997 A JP2006057997 A JP 2006057997A JP 2006057997 A JP2006057997 A JP 2006057997A JP 5175442 B2 JP5175442 B2 JP 5175442B2
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- yacon
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- anticancer agent
- anticancer
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- 239000000717 tumor promoter Substances 0.000 description 1
- 235000013976 turmeric Nutrition 0.000 description 1
- 238000009834 vaporization Methods 0.000 description 1
- 230000008016 vaporization Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 235000012773 waffles Nutrition 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 230000037303 wrinkles Effects 0.000 description 1
- 235000013618 yogurt Nutrition 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P60/00—Technologies relating to agriculture, livestock or agroalimentary industries
- Y02P60/80—Food processing, e.g. use of renewable energies or variable speed drives in handling, conveying or stacking
- Y02P60/87—Re-use of by-products of food processing for fodder production
Description
本発明は、ヤーコン由来の特定の活性成分を配合した抗ガン剤に関する。さらに詳しくは、本発明はヤーコン抽出画分に含まれる形態で有効な発ガン活性作用を抑制すべき疾患を治療または予防するための抗ガン剤に関するものである。 The present invention relates to an anticancer agent containing a specific active ingredient derived from yacon. More specifically, the present invention relates to an anticancer agent for treating or preventing a disease whose effective carcinogenic activity is to be suppressed in a form contained in a yacon extract fraction.
ガンは日本人の年間の死亡原因の1／4を占めるまたガンの発生要因の約80％が、我々の身近な環境的要因（化学物質）によるものであることが、疫学的研究からも明らかにされており、ヒトの発ガン因子のうち、約25％が食物であると言われている（非特許文献１）。日常摂取する食品が、一方ではガンの発生に、他方ではその抑制に大きく関わっていることは注目すべき事実であり、疫学的研究により示唆される野菜の発ガン抑制効果を発ガン予防の見地から、化学的に解明することは極めて意義深いことである（非特許文献２）。 Epidemiological studies show that cancer accounts for one-fourth of all causes of death in Japan and that approximately 80% of cancer causes are caused by environmental factors (chemical substances) that are familiar to us. About 25% of human carcinogenic factors are said to be food (Non-patent Document 1). It is a remarkable fact that foods taken daily are greatly involved in the development of cancer on the one hand, and on the other hand, and on the other hand, it is a remarkable fact. Therefore, chemical clarification is extremely significant (Non-patent Document 2).
化学物質による発ガンの発生の機構は発ガン二段階説によって理解されており、初発段階（イニシエーション）と促進段階（プロモーション）の二つの異なったプロセスが関与するというものである。イニシエーション過程とは、正常細胞が潜在的腫瘍細胞へと変化する過程であり、プロモーション過程とは、その潜在的腫瘍細胞が目に見える腫瘍細胞へと変化する過程である（非特許文献３、４）。化学発ガンを防止する手段として、このイニシエーション過程またはプロモーション過程のどちらか一方、またはその両方を化学物質によって抑制する方法があげられる（非特許文献５）。しかし、人間は成人になるとイニシエートされた細胞をすでに体内に保有していると考えられており、プロモーション過程を抑制する方が、化学発ガンを予防するうえでより効率的であると言える（非特許文献６)。 The mechanism of chemical carcinogenesis is understood by the two-stage carcinogenesis theory, and involves two different processes, the initial stage (initiation) and the promotion stage (promotion). The initiation process is a process in which normal cells change into potential tumor cells, and the promotion process is a process in which the potential tumor cells change into visible tumor cells (Non-Patent Documents 3 and 4). ). As a means for preventing chemical carcinogenesis, there is a method of suppressing one or both of the initiation process and the promotion process with a chemical substance (Non-patent Document 5). However, it is thought that humans already have initiated cells in the body when they become adults, and it can be said that suppressing the promotion process is more efficient in preventing chemical carcinogenesis (non- Patent Document 6).
これまでに単離された、天然に存在する抗ガン活性成分として、アオジソからオレアノール酸、ゴボウからモッコラクトンとアルクチン酸、ショウガからジンジャロール、茶からカテキン、ウコンからクルクミン、紫蘇抽からα−リノレン酸、ブロッコリーからスルフォラファン、ロ−ズマリーからロズマノールなどが知られる（非特許文献７、８）。また、膨大な数の疫学的調査や動物実験により、カンキツ類の果実にはガン予防効果があることが明らかにされている（非特許文献９）。
ヤーコン（Polymnia sonchifolia）は、南米アンデス地方を原産とするキク科の多年草であり、エクアドルからペルーにかけて分布している。日本では現在、各地で栽培されているが、やや冷涼な地方が適地と考えられ、本州では埼玉県などで栽培されている。また、アンデスポテトとも呼ばれ、地下部に貯蔵器官のサツマイモに似た塊根を形成する。
Naturally-occurring anti-cancer active ingredients that have been isolated so far include aojiso to oleanolic acid, burdock to moccolactone and alctinic acid, ginger to gingerol, tea to catechin, turmeric to curcumin, shiso extract to α-linolene. Acids, broccoli to sulforaphane, and rosemary to rosmanol are known (Non-Patent Documents 7 and 8). In addition, an enormous number of epidemiological studies and animal experiments have revealed that citrus fruits have a cancer-preventing effect (Non-Patent Document 9).
Yam (Polymnia sonchifolia) is a perennial asteraceae native to the Andes region of South America and is distributed from Ecuador to Peru. It is currently cultivated in various places in Japan, but a slightly cooler region is considered suitable, and in Honshu it is cultivated in Saitama Prefecture. Also called Andean potato, it forms tuberous roots similar to sweet potatoes in the underground.
ヤーコンの利用法として、葉や茎はお茶にして利用される。葉や茎には、カリウム・カルシウム等のミネラルやテルペン・タンニン・フラボノイド配糖体・イヌリン、ビタミンA、B1、B2、Cなど、生命維持に欠かすことのできない物質が豊富に含まれている。また、血糖の上昇を抑えるインスリンと同様の働きをする物質が含まれていることも分かってきた。ヤーコンの葉の注目すべきもう一つの機能性は、脂肪の代謝改善作用であり、ヤーコンのお茶を飲むことで中性脂肪、コレステロール値を下げ、結果的に体重増加の抑制につながるということが研究により証明されている。
また、塊根部は、前インカ時代から食用に供されていたようであり、甘味があり歯ごたえもよく、生でも食べられる。最も注目される特徴は、フラクトオリゴ糖を塊根に含むことであり、フラクトオリゴ糖の機能性としては、虫歯菌の抑制、ビフィズス菌の活性化、整腸作用、血中脂肪や血糖値の改善等があげられる。さらに、塊根部は、食物繊維や抗酸化作用のあるポリフェノールも豊富に含んでおり、機能性根菜として注目されている（非特許文献１０〜１４）。また、ヤーコンの塊根部からカフェー酸の誘導体も単離されている（非特許文献１５）。このように、ヤーコンについて、これまで様々な機能性が研究されてきている。しかし、抗発ガン性に関しては、未だ明らかにされていない。
As a method of using yacon, leaves and stems are used as tea. Leaves and stems are rich in minerals such as potassium and calcium, and terpenes, tannins, flavonoid glycosides, inulin, vitamins A, B 1 , B 2 , C, and other substances indispensable for life support. Yes. It has also been found that it contains substances that function similarly to insulin, which suppresses the increase in blood sugar. Another notable feature of yacon leaves is the ability to improve fat metabolism, and drinking yacon tea lowers triglycerides and cholesterol levels, resulting in suppression of weight gain. Proven by research.
The tuberous root seems to have been edible since the pre-Inca era, it is sweet and chewy and can be eaten raw. The most notable feature is the inclusion of fructooligosaccharides in tuberous roots. The functionalities of fructooligosaccharides include the inhibition of caries bacteria, the activation of bifidobacteria, the intestinal action, the improvement of blood fat and blood sugar levels, etc. can give. Furthermore, the tuberous root part contains abundant dietary fiber and polyphenols having an antioxidant action, and has attracted attention as a functional root vegetable (Non-Patent Documents 10 to 14). A derivative of caffeic acid has also been isolated from the root of yacon (Non-patent Document 15). Thus, various functionalities have been studied for yacon. However, the anti-carcinogenicity has not been clarified yet.
ヤーコンには、前記したように、様々な生理活性があることが確かめられてきたがその生理活性の中に抗発ガン活性は含まれておらず、ヤーコンが抗ガン活性作用を呈するということはこれまで知られていなかった。 As mentioned above, it has been confirmed that yacon has various physiological activities, but the anti-carcinogenic activity is not included in the physiological activities, and that yacon exhibits an anti-cancer activity. It was not known so far.
本発明は、安全性に問題がなく、安価で比較的容易に入手可能な材料、好ましくは未利用材料であるヤーコンの芋皮および／または葉茎部から、優れた抗ガン活性作用を有する組成物を提供すること、好ましくは発ガン活性作用を抑制すべき疾患を治療または予防するための組成物、より具体的には食品添加物、食品素材、飲食品、医薬品・医薬部外品および飼料からなる群から選ばれる形態のものを提供することを課題とする。 The present invention is a composition having an excellent anticancer activity from a cheap and relatively easily available material, preferably a yacon crust and / or leaf stem part, which is an unused material. Composition for providing a product, preferably treating or preventing a disease whose carcinogenic activity should be suppressed, more specifically food additive, food material, food and drink, pharmaceutical / quasi-drug and feed It is an object to provide a form selected from the group consisting of:
本発明は以下の（１）〜（４）の抗ガン剤を要旨とする。
（１）ヤーコン由来の9-アセトキシ-10(2,3-ジメチル-オキシランカルボニルオキシ)-4メチル-12-メチレン-13-オキソ-3,14-ジオキサ-ロリシクロ[9.3.0.02,4]テトラデ-7-セン-8-カルボン酸メチルエステルを有効成分とする抗ガン剤。
（２）ヤーコンがヤーコンの芋皮および／または葉茎部である上記（１）の抗ガン剤。
（３）抗ガン剤が、発ガン活性作用を阻害すべき疾患を治療または予防するための剤である上記（１）または（２）の抗ガン剤。
（４）上記発ガン活性作用を阻害すべき疾患が、腫瘍もしくは癌における発ガン活性作用が原因となる疾患である（３）の抗ガン剤。
The gist of the present invention is the following anticancer agents (1) to ( 4 ).
(1) 9-acetoxy-10 (2,3-dimethyl-oxiranecarbonyloxy) -4 methyl-12-methylene-13-oxo-3,14-dioxa-loricyclo [9.3.0.0 2,4 ] tetrade derived from Yacon Anticancer agent containing -7-sen-8-carboxylic acid methyl ester as an active ingredient.
(2) The anticancer agent according to the above (1), wherein the yacon is scab and / or leaf stem portion of yacon.
( 3 ) The anticancer agent according to (1) or (2) above, wherein the anticancer agent is an agent for treating or preventing a disease whose carcinogenic activity is to be inhibited.
( 4 ) The anticancer agent according to ( 3 ), wherein the disease that should inhibit the carcinogenic activity is a disease caused by the carcinogenic activity in a tumor or cancer.
本発明は、安全性に問題がなく、安価で比較的容易に入手可能な材料（未利用材料であるヤーコンの芋皮および／または葉茎部）から、副作用が少ない、優れた抗ガン活性作用を有する組成物を提供すること、好ましくは発ガン活性作用を抑制すべき疾患を治療または予防するための組成物、より具体的には食品添加物、食品素材、飲食品、医薬品・医薬部外品および飼料からなる群から選ばれる形態のものを提供することができる。 The present invention has an excellent anticancer activity with few side effects from materials that are safe and inexpensive and relatively easily available (unused material, yak crust and / or leaf stem). A composition for treating or preventing a disease whose carcinogenic activity should be suppressed, more specifically, a food additive, a food material, a food or drink, a pharmaceutical product or a quasi-drug The thing of the form chosen from the group which consists of goods and feed can be provided.
ヤーコンは、葉、茎、葉茎部（葉柄）などのヤーコン地上部と芋が使用できるが、芋皮や葉茎部は未利用部分であり、該未利用部分を用いることはヤーコンの高度有効利用の観点から望ましい。使用にあたっては、芋皮や葉茎部のヤーコン未利用部分を乾燥したものを細切りあるいは粉末にして直接用いる。ヤーコン中の成分では熱による変性を受けやすい成分と安定な成分があり、乾燥条件や抽出条件によって抽出される成分が異なってくる。前処理工程で十分乾燥することと、できるだけ熱変性の起こらない低温で行うことが望ましい。 Yacon can be used on the ground and cocoons such as leaves, stems, and leaf stems (petiole), but the husks and leaf stems are unused parts, and it is highly effective to use these unused parts. Desirable from the viewpoint of use. In use, dry dried konkon portions of the crust and leaf stems are directly used after chopping or powdering. Among the components in yacon, there are components that are susceptible to denaturation by heat and stable components, and the components that are extracted differ depending on the drying conditions and extraction conditions. It is desirable to dry sufficiently in the pretreatment step and to perform at a low temperature where heat denaturation does not occur as much as possible.
本発明の上記組成物は、安全性に問題がなく、安価で比較的容易に入手可能な材料（未利用材料であるヤーコンの芋皮および／または葉茎部）から、工場規模での実生産に適した簡便な処理方法により得られ、その生体への適用は飲食物、医薬品、肥料、飼料や皮膚外用剤に使用することで、優れた発ガン活性抑制効果を得ることが期待できる。
本発明の上記組成物は、発ガン活性抑制作用を有する天然物由来の活性成分を有するものであり、該活性成分に基づく発ガン活性抑制を応用することにより、たとえば安全なガンの治療法へと導くのであり、発ガン活性抑制の作用は、腫瘍もしくはガンにおける発ガン活性作用が原因となる疾患に対して予防および安全に治療する効果を有する機能性組成物である。
すなわち、本発明の上記組成物は、発ガン活性を抑制すべき疾患を治療または予防するための組成物である。発ガン活性を抑制すべき疾患とは、発ガン活性が病態の発生に重要な働きをしている疾患であれば、どのようなものでも対象となる。したがって、発ガン活性を抑制すべき疾患は、腫瘍もしくはガンにおける発ガン活性作用が原因となる疾患である。本発明においては、発ガン活性を抑制すべき疾患として、種々の腫瘍またはガンを標的とすることが好ましい。
The above-mentioned composition of the present invention can be produced on a factory scale from materials that are safe and inexpensive and relatively easily available (unused materials such as yak crust and / or leaf stem). It can be obtained by a simple treatment method suitable for use in the living body, and can be expected to obtain an excellent carcinogenic activity suppressing effect when used for foods, beverages, pharmaceuticals, fertilizers, feeds and skin external preparations.
The composition of the present invention has an active ingredient derived from a natural product having a carcinogenic activity suppressing action, and by applying the carcinogenic activity suppressing based on the active ingredient, for example, to a safe cancer treatment method. The action of inhibiting carcinogenic activity is a functional composition having an effect of preventing and safely treating a disease caused by the carcinogenic activity of a tumor or cancer.
That is, the composition of the present invention is a composition for treating or preventing a disease whose carcinogenic activity should be suppressed. As the disease whose carcinogenic activity should be suppressed, any disease can be used as long as the carcinogenic activity plays an important role in the pathogenesis. Therefore, a disease whose carcinogenic activity is to be suppressed is a disease caused by a carcinogenic activity in a tumor or cancer. In the present invention, it is preferable to target various tumors or cancers as diseases for which carcinogenic activity is to be suppressed.
本発明の上記組成物は、ヤーコン由来の成分を抗ガン活性作用の有効成分とすることを特徴とする。前記ヤーコン由来の成分に含まれる抗ガン活性作用を呈する物質は、好ましくはヤーコンの芋皮および／または葉茎部のヘキサン抽出物に含まれる物質である。 The composition according to the present invention is characterized in that a component derived from yacon is used as an active ingredient having an anticancer activity. The substance exhibiting an anti-cancer activity contained in the component derived from yacon is preferably a substance contained in a hexane extract of yak crust and / or leaf stem.
ヤーコンにおける最適抽出溶媒と最適部位の比較検討においては、乾燥済みのヤーコンの葉、芋、皮、また生の状態のヤーコンの芋、皮を粉砕後、それぞれヘキサン、アセトン、70％MeOH水溶液の溶媒で抽出し、抗ガン活性試験に供した。その結果、葉の部分は、いずれの抽出溶媒においても強い活性がみられた。乾燥済みの皮の部分にも強い活性がみられたが、細胞毒性試験の結果より、葉の部分よりも毒性が強いと考えられた。他の部位においてはヘキサン抽出物が最も強い活性を示した。これらの結果より、最適抽出溶媒はヘキサン、最適部位は葉であると考えられた。
また、塊根部のみに注目すると、全体的に芋の部分よりも皮の部分の方が、活性が強かったことから、抗ガン活性成分を有しているのは、皮の部分であると言える。
また、ヤーコンの葉について抗ガン活性成分を単離した。単離した成分は、組成式C23H28O10、分子量464の9-アセトキシ-10(2,3-ジメチル-オキシランカルボニルオキシ)-4メチル-12-メチレン-13-オキソ-3,14-ジオキサ-ロリシクロ[9.3.0.02,4]テトラデ-7-セン-8-カルボン酸メチルエステル（9-Acetoxy-10-（2，3−dimethyl-oxiranecarbonyloxy）-4-methyl-12-methylene-13-oxo-3,14-dioxa-tricyclo[9.3.0.02,4]tetradec-7-ene-8-carboxylic acid methyl ester）であった。この成分は、強い抗菌活性を示す（Biosci・Biotecbnol．Biochem．，67（10），p2154−2159（2003）、Phytochemistry，Vol．39 No．4，p845-848（1995）、Phytochemistry，Vol．38，No．2，p433−435（1995）、Phytochemistry, Vol. 43, No. 5, p1019-1021（1996））ことがすでに分かっているが、抗ガン活性については未だ明らかにされていない。
また、この単離された活性成分について、すでに抗ガン活性成分として単離されているクルクミンと比較したところ、クルクミンがTPAに対して、100倍の濃度でRaji細胞の変形を完全に抑制したのに対し、ヤーコンの活性成分においては、さらに10倍薄い濃度で強い活性がみられた。このことから、ヤーコンから単離された成分は、強い抗ガン活性を示すと思われる。
また、細胞毒性試験の結果を見ると、クルクミンがRaji細胞の変形を完全に抑制した100倍の濃度で生育率が19％であったのに対し、活性成分においては、変形を完全に抑制した濃度で平均30％弱の生育率であった。このことから、細胞に対する毒性もクルクミンと比較すると低いと言える。
In the comparative examination of the optimum extraction solvent and the optimum part in Yacon, after drying dried Yacon leaves, straw, and skin, or fresh Yacon straw and skin, hexane, acetone, and 70% MeOH aqueous solvent respectively And subjected to anti-cancer activity test. As a result, the leaf portion showed strong activity in any extraction solvent. A strong activity was also observed in the dried skin part, but from the results of the cytotoxicity test, it was considered to be more toxic than the leaf part. At other sites, the hexane extract showed the strongest activity. From these results, it was considered that the optimum extraction solvent was hexane and the optimum site was leaves.
In addition, when focusing only on the tuberous root part, the skin part was generally more active than the wrinkle part, so it can be said that the skin part has the anticancer active ingredient. .
In addition, anticancer active ingredients were isolated from yacon leaves. The isolated component is composed of 9-acetoxy-10 (2,3-dimethyl-oxiranecarbonyloxy) -4methyl-12-methylene-13-oxo-3,14- having the composition formula C 23 H 28 O 10 and a molecular weight of 464. Dioxa-rolicyclo [9.3.0.0 2,4 ] tetrade-7-cene-8-carboxylic acid methyl ester (9-Acetoxy-10- (2,3-dimethyl-oxiranecarbonyloxy) -4-methyl-12-methylene-13- oxo-3,14-dioxa-tricyclo [9.3.0.0 2,4 ] tetradec-7-ene-8-carboxylic acid methyl ester). This component exhibits strong antibacterial activity (Biosci Biotecbnol. Biochem., 67 (10), p2154-1159 (2003), Phytochemistry, Vol. 39 No. 4, p845-848 (1995), Phytochemistry, Vol. 38. , No. 2, p433-435 (1995), Phytochemistry, Vol. 43, No. 5, p1019-1021 (1996)), but anticancer activity has not yet been clarified.
In addition, when this isolated active ingredient was compared with curcumin, which had already been isolated as an anti-cancer active ingredient, curcumin completely suppressed the deformation of Raji cells at 100 times the concentration of TPA. On the other hand, the active component of Yacon showed strong activity at a concentration 10 times thinner. This suggests that the component isolated from yacon exhibits strong anticancer activity.
In addition, the results of the cytotoxicity test showed that curcumin completely inhibited the deformation of Raji cells and the growth rate was 19% at 100 times the concentration, whereas the active ingredient completely suppressed the deformation. The average growth rate was less than 30%. From this, it can be said that the toxicity to cells is low compared to curcumin.
単離された活性成分あるいはヤーコンヘキサン抽出物は、発ガン活性作用を抑制するための食品添加物、食品素材、飲食品、医薬品・医薬部外品および飼料からなる群から選ばれる形態のものである。その組成物の機能性を生かして健康飲食品、患者用栄養飲食品を謳った食品、同様に、家畜、家禽、魚などの飼育動物のための飼料の開発が可能となった。
すなわち、上記飲食品が、抗ガン活性作用を有する、機能性食品、栄養補助食品または健康飲食品である。上記飼料が、抗ガン活性作用を有する、家畜、家禽、ペット類の飼料である。具体的には、上述したヤーコンヘキサン抽出物を含む食品素材を、食品形態、飲料形態または飼料形態のいずれの形態で使用することができる。
本発明の抗ガン活性作用を有する組成物が有する上述した機能性を生かして用いる場合は、その含量は、特に制限されないが、目的とする機能の度合い、使用態様、使用量等により適宜調整することができ、例えば０．００１〜１００質量％である。抗ガン活性作用を有する組成物は、人体やその他飲食物、医薬品、飼料や皮膚外用剤に使用することができる。また、経口等により内服することも、皮膚等に塗布することもできる。常法にしたがって経口、非経口の製品に配合することができ、調味料、食品添加物、食品素材、飲食品、健康飲食品、皮膚外用剤、医薬品および飼料等の様々な分野で利用することができる。例えば、飲食物に配合した場合には、発ガン活性作用を抑制すべき疾患を治療または予防するための飲食物を提供することができる。予防等の効果からは、健康食品、栄養食品等として用いられることも期待できる。その他、家畜、および／または魚類の飼料、餌料に利用することができる。人体やその他飲食物、医薬品、肥料、飼料や皮膚外用剤に使用することにより、発ガン活性作用を抑制すべき疾患を治療または予防する効果を得ることができる。
さらに、未利用のヤーコン部位（ヤーコンの芋皮および／または葉茎部）から容易に得ることができ、コスト面からみても、資源の有効活用という面からみても好ましい。
The isolated active ingredient or yacon hexane extract is in a form selected from the group consisting of food additives, food materials, foods and drinks, pharmaceuticals / quasi-drugs and feeds for suppressing carcinogenic activity. is there. Utilizing the functionality of the composition, it has become possible to develop healthy foods and drinks, foods containing nutritional foods and drinks for patients, and feeds for domestic animals such as livestock, poultry and fish.
That is, the food / beverage product is a functional food, nutritional supplement or health food / beverage product having an anticancer activity. The feed is feed for livestock, poultry and pets having an anti-cancer activity. Specifically, the food material containing the above-described yacon hexane extract can be used in any form of food, beverage or feed.
In the case of using the above-described functionality of the composition having anticancer activity of the present invention, the content is not particularly limited, but is appropriately adjusted depending on the degree of intended function, usage mode, usage amount, etc. For example, 0.001 to 100% by mass. The composition having an anticancer activity can be used for the human body, other foods and drinks, pharmaceuticals, feeds and skin external preparations. It can also be taken orally or applied to the skin. Can be incorporated into oral and parenteral products according to conventional methods and used in various fields such as seasonings, food additives, food ingredients, food and drink, health food and drink, topical skin preparations, pharmaceuticals and feed Can do. For example, when blended in food or drink, food or drink for treating or preventing a disease whose carcinogenic activity should be suppressed can be provided. From the effect of prevention, it can be expected to be used as health food, nutritional food and the like. In addition, it can be used for livestock and / or fish feed and feed. By using it in the human body, other foods and drinks, pharmaceuticals, fertilizers, feeds and skin external preparations, it is possible to obtain an effect of treating or preventing a disease whose carcinogenic activity is to be suppressed.
Furthermore, it can be easily obtained from an unused yacon site (a yak crust and / or leaf stem), which is preferable from the viewpoint of cost and effective utilization of resources.
本発明の組成物を食品に利用する場合、そのままの形態、オイルなどに希釈した形態、乳液状形態食、または食品業界で一般的に使用される担体を添加した形態などのものを調製してもよい。
乳液状形態のものは、例えば、油相部に組成物を添加し、更にグリセリン脂肪酸エステル、ソルビタン脂肪酸エステル、ショ糖脂肪酸エステル、グリセロール、デキストリン、ナタネ油、大豆油、コーン油などの液状の脂肪を加え、水相部にＬ−アスコルビン酸或いはそのエステルまたは塩、例えばローカストビーンガム、アラビアガムまたはゼラチンなどのガム質、例えばヘスペリジン、ルチン、ケルセチン、カテキン、チアニジンなどのフラボノイド類またはポリフェノール類或いはその混合物などを添加し、乳化することによって調製できる。
When the composition of the present invention is used for food, it can be prepared as it is, in a form diluted with oil, a milk form meal, or a form to which a carrier generally used in the food industry is added. Also good.
In the form of an emulsion, for example, a composition is added to the oil phase, and liquid fats such as glycerin fatty acid ester, sorbitan fatty acid ester, sucrose fatty acid ester, glycerol, dextrin, rapeseed oil, soybean oil, corn oil, etc. L-ascorbic acid or its ester or salt, for example, gum such as locust bean gum, gum arabic or gelatin, for example, flavonoids such as hesperidin, rutin, quercetin, catechin, thianidine or polyphenols or the like It can be prepared by adding a mixture and emulsifying.
飲料の形態は、非アルコール飲料またはアルコール飲料である。非アルコール飲料としては、例えば、炭酸系飲料、果汁飲料、ネクター飲料などの非炭酸系飲料、清涼飲料、スポーツ飲料、茶、コーヒー、ココアなど、また、アルコール飲料の形態ではスピリッツ、リキュール、チューハイ、果実酒類、麦酒、発泡酒、薬用酒などの一般食品の形態を挙げることができる。 The form of the beverage is a non-alcoholic beverage or an alcoholic beverage. Non-alcoholic beverages include, for example, non-carbonated beverages such as carbonated beverages, fruit juice beverages, and nectar beverages, soft drinks, sports beverages, tea, coffee, cocoa, etc. The form of general foods, such as fruit liquor, barley liquor, Happoshu, and medicinal liquor, can be mentioned.
飲食物としては、具体的には以下のものを例示することができる。洋菓子類（プリン、ゼリー、グミキャンディー、キャンディー、ドロップ、キャラメル、チューインガム、チョコレート、ペストリー、バタークリーム、カスタードグリーム、シュークリーム、ホットケーキ、パン、ポテトチップス、フライドポテト、ポップコーン、ビスケット、クラッカー、パイ、スポンジケーキ、カステラ、ワッフル、ケーキ、ドーナツ、ビスケット、クッキー、せんべい、おかき、おこし、まんじゅう、あめなど）、乾燥麺製品（マカロニ、パスタ）、卵製品（マヨネーズ、生クリーム）、飲料（機能性飲料、乳酸飲料、乳酸菌飲料、濃厚乳性飲料、果汁飲料、無果汁飲料、果肉飲料、透明炭酸飲料、果汁入り炭酸飲料、果実着色炭酸飲料）、嗜好品（緑茶、紅茶、インスタントコーヒー、ココア、缶入りコーヒードリンク）、乳製品（アイスクリーム、ヨーグルト、コーヒー用ミルク、バター、バターソース、チーズ、発酵乳、加工乳）、ペースト類（マーマレード、ジャム、フラワーペースト、ピーナッツペースト、フルーツペースト、果実のシロップ漬け）、畜肉製品（ハム、ソーセージ、ベーコン、ドライソーセージ、ビーフジャーキー、ラード）、魚介類製品（魚肉ハム、魚肉ソーセージ、蒲鉾、ちくわ、ハンペン、魚の干物、鰹節、鯖節、煮干し、うに、いかの塩辛、スルメ、魚のみりん干し、貝の干物、鮭などの燻製品）、佃煮類（小魚、貝類、山菜、茸、昆布）、カレー類（即席カレー、レトルトカレー、缶詰カレー）、調味料剤（みそ、粉末みそ、醤油、粉末醤油、もろみ、魚醤、ソース、ケチャップ、オイスターソース、固形ブイヨン、焼き肉のたれ、カレールー、シチューの素、スープの素、だしの素、ペースト、インスタントスープ、ふりかけ、ドレッシング、サラダ油）、揚げ製品（油揚げ、油揚げ菓子、即席ラーメン）、豆乳、マーガリン、ショートニングなどを挙げることができる。 Specific examples of food and drink include the following. Pastry (pudding, jelly, gummy candy, candy, drop, caramel, chewing gum, chocolate, pastry, butter cream, custard cream, cream puff, hot cake, bread, potato chips, french fries, popcorn, biscuits, crackers, pie, sponge Cakes, castella, waffles, cakes, donuts, biscuits, cookies, rice crackers, rice crackers, rice cakes, manju, candy, etc., dried noodle products (macaroni, pasta), egg products (mayonnaise, fresh cream), beverages (functional beverages, Lactic acid beverages, lactic acid bacteria beverages, concentrated milk beverages, fruit juice beverages, fruitless beverages, pulp beverages, transparent carbonated beverages, carbonated beverages with fruit juice, fruit colored carbonated beverages), luxury products (green tea, tea, instant coffee, cocoa, canned Coffee Milk), dairy products (ice cream, yogurt, coffee milk, butter, butter sauce, cheese, fermented milk, processed milk), pastes (marmalade, jam, flower paste, peanut paste, fruit paste, fruit syrup) , Livestock products (ham, sausage, bacon, dry sausage, beef jerky, lard), seafood products (fish meat ham, fish sausage, salmon, chikuwa, hampen, dried fish, bonito, bonito, boiled, sea urchin Salted fish, plums, dried fish, shellfish, salmon products such as salmon), boiled fish (small fish, shellfish, wild vegetables, salmon, kelp), curry (instant curry, retort curry, canned curry), seasoning (Miso, powdered miso, soy sauce, powdered soy sauce, moromi, fish sauce, sauce, ketchup, oyster sauce, solid bouillon List of grilled meat sauce, curry roux, stew sauce, soup sauce, dashi stock, paste, instant soup, sprinkle, dressing, salad oil), fried products (fried food, fried sweets, instant ramen), soy milk, margarine, shortening, etc. be able to.
上記飲食物は、組成物を常法に従って、一般食品の原料と配合することにより、加工製造することができる。 The said food and drink can be processed and manufactured by mix | blending a composition with the raw material of a general food according to a conventional method.
上記飲食物への組成物の配合量は食品の形態により異なり特に限定されるものではないが、通常は０．００１〜２０％が好ましい。 Although the compounding quantity of the composition to the said food-drinks changes with forms of food and is not specifically limited, Usually, 0.001 to 20% is preferable.
上記飲食物は、機能性食品、栄養補助食品或いは健康食品類としても用いることができる。その形態は、特に限定されるものではなく、例えば、食品の製造例としては、アミノ酸バランスのとれた栄養価の高い乳蛋白質、大豆蛋白質、卵アルブミンなどの蛋白質、これらの分解物、卵白のオリゴペプチド、大豆加水分解物などの他、アミノ酸単体の混合物などを、常法に従って使用することができる。また、ソフトカプセル、タブレットなどの形態で利用することもできる。 The above food and drink can also be used as functional foods, nutritional supplements or health foods. The form is not particularly limited, and examples of food production include milk proteins with high amino acid balance, soy protein, and proteins such as egg albumin, degradation products thereof, and egg white oligos. In addition to peptides, soybean hydrolysates, and the like, mixtures of amino acids alone can be used according to conventional methods. It can also be used in the form of a soft capsule, a tablet or the like.
栄養補助食品或いは機能性食品の例としては、糖類、脂肪、微量元素、ビタミン類、乳化剤、香料などが配合された流動食、半消化態栄養食、成分栄養食、ドリンク剤、カプセル剤、経腸栄養剤などの加工形態を挙げることができる。上記各種食品には、例えば、スポーツドリンク、栄養ドリンクなどの飲食物は、栄養バランス、風味を良くするために、更にアミノ酸、ビタミン類、ミネラル類などの栄養的添加物や甘味料、香辛料、香料、色素などを配合することもできる。 Examples of dietary supplements or functional foods include liquid foods, semi-digested nutritional foods, ingredient nutritional foods, drinks, capsules, and sucrose containing sugars, fats, trace elements, vitamins, emulsifiers, and fragrances. Processing forms such as enteral nutrients can be mentioned. In the above-mentioned various foods, for example, foods and drinks such as sports drinks and nutritional drinks are further supplemented with nutritional additives such as amino acids, vitamins and minerals, sweeteners, spices and fragrances to improve nutritional balance and flavor. , Pigments and the like can also be blended.
本発明の組成物を安定化させるために抗酸化剤、例えば、トコフェロール、Ｌ−アスコルビン酸、ＢＨＡ、ローズマリー抽出物などを常法に従って併用することができる。 In order to stabilize the composition of the present invention, an antioxidant such as tocopherol, L-ascorbic acid, BHA, rosemary extract and the like can be used in combination according to a conventional method.
本発明の組成物は、家畜、家禽、ペット類の飼料用に応用することができる。例えば、ドライドッグフード、ドライキャットフード、ウェットドッグフード、ウェットキャットフード、セミモイストドックフード、養鶏用飼料、牛、豚などの家畜用飼料に配合することができる。飼料自体は、常法に従って調製することができる。
これらの治療剤および予防剤は、ヒト以外の動物、例えば、牛、馬、豚、羊などの家畜用哺乳類、鶏、ウズラ、ダチョウなどの家禽類、は虫類、鳥類或いは小型哺乳類などのペット類、養殖魚類などにも用いることができる。
The composition of the present invention can be applied to feed for livestock, poultry and pets. For example, it can mix | blend with livestock feeds, such as dry dog food, dry cat food, wet dog food, wet cat food, semi-moist dock food, poultry feed, cattle, and pigs. The feed itself can be prepared according to a conventional method.
These therapeutic agents and prophylactic agents include non-human animals, for example, domestic mammals such as cattle, horses, pigs and sheep, poultry such as chickens, quails and ostriches, pets such as reptiles, birds and small mammals, It can also be used for farmed fish.
抗ガン活性作用を利用する薬剤について説明する。
抗ガン活性成分を有効成分とする、前記諸症状の予防剤または治療剤は、これらのみで用いるほか、一般的賦形剤、安定剤、保存剤、結合剤、崩壊剤等の適当な添加剤を配合し、液剤、カプセル剤、顆粒剤、丸剤、散剤、錠剤等の適宜な剤型を選んで製剤し、経口的あるいは経腸的に投与することができる。
A drug utilizing an anticancer activity will be described.
The preventive or therapeutic agent for the above-mentioned various symptoms, which contains an anti-cancer active ingredient as an active ingredient, is used alone, and appropriate additives such as general excipients, stabilizers, preservatives, binders, disintegrants, etc. Can be formulated by selecting an appropriate dosage form such as liquid, capsule, granule, pill, powder, tablet and the like, and can be administered orally or enterally.
本発明の抗ガン活性作用を利用する薬剤を臨床に適用するに際しては、有効成分として9-アセトキシ-10(2,3-ジメチル-オキシランカルボニルオキシ)-4メチル-12-メチレン-13-オキソ-3,14-ジオキサ-ロリシクロ[9.3.0.02,4］テトラデ-7-セン-8-カルボン酸メチルエステルおよびその誘導体を、固体、半個体又は液体の医薬用担体又は希釈剤、例えば、賦形剤、安定剤等の添加剤とともに含む製剤とすることが好ましい。該医薬製剤において、前記有効成分の担体成分に対する割合は、１〜90重量％の間で変動させうる。剤形及び投与形態としては、顆粒剤、細粒剤、散剤、錠剤、カプセル剤、丸剤もしくは液剤等の剤形にして、又は原末のまま経口投与してもよい。 When the drug utilizing the anticancer activity of the present invention is applied clinically, 9-acetoxy-10 (2,3-dimethyl-oxiranecarbonyloxy) -4methyl-12-methylene-13-oxo- 3,14-Dioxa-loricyclo [9.3.0.0 2,4 ] tetrade-7-cene-8-carboxylic acid methyl ester and its derivatives are converted into solid, semi-solid or liquid pharmaceutical carriers or diluents, for example shaped It is preferable to prepare a preparation containing additives such as an agent and a stabilizer. In the pharmaceutical preparation, the ratio of the active ingredient to the carrier component can vary between 1 and 90% by weight. The dosage form and dosage form may be a granule, fine granule, powder, tablet, capsule, pill or liquid, or may be orally administered as the bulk.
経口、経腸投与に適した医薬用の有機又は無機の、固体、半個体又は液体の担体、溶解剤もしくは希釈剤を、本発明の血糖上昇抑制剤を調製するために用いることができる。水、ゼラチン、乳糖、澱粉、ステアリン酸マグネシウム、タルク、動植物油脂、ベンジルアルコール、ガム、ポリアルキレングリコール、石油樹脂、やし油、ラノリン、又は医薬に用いられる他のキャリアー (担体) は全て、本発明の抗ガン活性作用を利用する薬剤の担体として用いることができる。また、安定剤、湿潤剤、乳化剤や、浸透圧を変えたり、配合剤の適切なpＨを維持するための塩類を補助薬剤として適宜用いることもできる。 Pharmaceutical organic or inorganic solid, semi-solid or liquid carriers, solubilizers or diluents suitable for oral and enteral administration can be used to prepare the antihyperglycemic agent of the present invention. All water, gelatin, lactose, starch, magnesium stearate, talc, animal and vegetable oils, benzyl alcohol, gum, polyalkylene glycol, petroleum resin, palm oil, lanolin, or other carriers used in medicine are all It can be used as a drug carrier utilizing the anticancer activity of the invention. In addition, stabilizers, wetting agents, emulsifiers, and salts for changing the osmotic pressure or maintaining an appropriate pH of the compounding agent can be appropriately used as auxiliary agents.
更に、本発明の抗ガン活性作用を利用する薬剤は、ガンなどの治療において、本発明の抗ガン活性作用を利用する薬剤とともに適切に投与することができる他の医薬として有効な成分、例えば他の適当な抗ガン活性作用を利用する薬剤を含有していてもよい。顆粒剤、細粒剤、散剤、錠剤又はカプセル剤の場合には、本発明の抗ガン活性作用を利用する薬剤は9-アセトキシ-10(2,3-ジメチル-オキシランカルボニルオキシ)-4メチル-12-メチレン-13-オキソ-3,14-ジオキサ-ロリシクロ[9.3.0.02,4］テトラデ-7-セン-8-カルボン酸メチルエステルおよびその誘導体を５〜80重量％含有しているのが好ましく、液剤の場合には、対応する量 (割合) は、１〜30重量％であるのが好ましい。 Furthermore, the drug utilizing the anti-cancer activity of the present invention is another pharmaceutical active ingredient that can be appropriately administered together with the drug utilizing the anti-cancer activity of the present invention in the treatment of cancer etc. It may contain a drug that utilizes an appropriate anticancer activity. In the case of granules, fine granules, powders, tablets or capsules, the drug utilizing the anticancer activity of the present invention is 9-acetoxy-10 (2,3-dimethyl-oxiranecarbonyloxy) -4 methyl- It contains 5 to 80% by weight of 12-methylene-13-oxo-3,14-dioxa-loricyclo [9.3.0.0 2,4 ] tetrade-7-cene-8-carboxylic acid methyl ester and its derivatives. Preferably, in the case of a liquid preparation, the corresponding amount (ratio) is preferably 1 to 30% by weight.
臨床投与量は、経口投与の場合、成人に対し9-アセトキシ-10(2,3-ジメチル-オキシランカルボニルオキシ)-4メチル-12-メチレン-13-オキソ-3,14-ジオキサ-ロリシクロ[9.3.0.02,4］テトラデ-7-セン-8-カルボン酸メチルエステルおよびその誘導体として、１日量0.3〜50ｇを内服するのが好ましいが、年令、症状により適宜増減することも可能である。前記１日量の本発明の血糖上昇抑制剤は、１日に１回、又は適当な間隔をおいて１日２もしくは３回に分けて、あるいは食前、食後あるいは食事とともに投与することが好ましい。 The clinical dose is 9-acetoxy-10 (2,3-dimethyl-oxiranecarbonyloxy) -4methyl-12-methylene-13-oxo-3,14-dioxa-loricyclo [9.3 for adults when administered orally. .0.0 2,4 ] tetrade-7-cene-8-carboxylic acid methyl ester and derivatives thereof are preferably taken in an amount of 0.3 to 50 g per day, but may be appropriately increased or decreased depending on age and symptoms. . The daily dose of the blood glucose elevation inhibitor of the present invention is preferably administered once a day, or divided into 2 or 3 times a day at an appropriate interval, or before, after or with a meal.
本発明の詳細を実施例で説明する。本発明はこれらの実施例によってなんら限定されるものではない。 Details of the present invention will be described in the examples. The present invention is not limited to these examples.
（ヤーコンの部位による抗ガン活性の違い）
本試験では、ヤーコンの未だ明らかにされていない抗ガン活性について、より詳細に調べるため、様々な部位について活性成分を抽出し、抗ガン活性試験に供することで、最適抽出溶媒と最適部位を決定した。
(Difference in anticancer activity depending on the site of Yacon)
In this study, in order to investigate in detail the anticancer activity of Yacon that has not yet been clarified, the optimal extraction solvent and the optimal site are determined by extracting active ingredients from various sites and subjecting them to an anticancer activity test. did.
［はじめに］
化学発ガンには、初発段階（イニシエーション）と促進段階（プロモーション）の二つの異なったプロセスが関与するというものである。プロモーション作用抑制の簡便な検出方法として、EBV（Epstein−Barr virus）を用いた実験系が確立されている。
EBV早期抗原検出法として、Raji細胞を用いたEBV活性化抑制試験法が用いられている。Raji細胞とは、EBVのゲノムを有するが、EBV粒子を産生しない細胞で、早期抗原を発現しておらずイニシエーションされた状態にある（「生化学実験」第17章，p255）。
本試験では、近藤らが開発したEBV早期抗原検出改良法（日農化1995年度大会要旨，166（1995））を用いて、ヤーコンの抗ガン活性を測定した。この方法は、Raji細胞にプロモーターとしてTPA（12-0-tetradecanoylphorbol 13-acetate）とn-酪酸ナトリウムを加えることにより、EBVが活性化され、球状の細胞が肥大、扁平化や周辺部の樹枝状化を伴う形態変化を示す現象を利用したものである。この検出系に被験物質を共存させ、形態変化抑制率を測定することで、被験物質の抗ガン活性を測定することができる。
[Introduction]
Chemical cancer involves two different processes, the initial phase (initiation) and the promotion phase (promotion). An experimental system using EBV (Epstein-Barr virus) has been established as a simple detection method for suppressing the promotion action.
As an EBV early antigen detection method, an EBV activation inhibition test method using Raji cells is used. A Raji cell is a cell that has an EBV genome but does not produce EBV particles and does not express an early antigen and is in an initiated state ("Biochemical Experiments", Chapter 17, p255).
In this study, Yacon's anticancer activity was measured using an improved EBV early antigen detection method developed by Kondo et al. In this method, by adding TPA (12-0-tetradecanoylphorbol 13-acetate) and sodium n-butyrate as promoters to Raji cells, EBV is activated, and spherical cells are enlarged, flattened and dendritic in the surrounding area. This is a phenomenon that utilizes a phenomenon showing a morphological change accompanied by crystallization. The anticancer activity of the test substance can be measured by allowing the test substance to coexist in this detection system and measuring the morphological change inhibition rate.
［実験方法］
試料の調製
今回用いた試料は、ヤーコンの葉(FD乾燥、30g)、ヤーコンの芋の部分(乾燥、27g)、ヤーコンの皮の部分(乾燥、17g)、ヤーコンの芋の部分(生、555.0g)、ヤーコンの皮の部分(生、158.7g)の5種類である。
[experimental method]
Sample preparation The samples used here were yacon leaves (FD dried, 30 g), yacon cocoon parts (dried, 27 g), yacon skin parts (dried, 17 g), yacon cocoon parts (raw, 555.0 g), yacon skin (raw, 158.7g).
最適抽出溶媒と最適部位の決定
調製した試料をミキサーで粉砕したものを3つに分けて、それぞれヘキサン、アセトン、70％MeOH水溶液に浸漬し抽出液を得た後、濃縮乾固した。
Determination of optimum extraction solvent and optimum site The prepared sample was pulverized with a mixer and divided into three parts, each was immersed in hexane, acetone and 70% MeOH aqueous solution to obtain an extract, and then concentrated to dryness.
抗発ガンプロモーター活性試験用試料の調製
濃縮乾固した試料から一部をとり、これをTPA（4μg/ml）の濃度に対して1000倍、200倍になるように、dimethyl sulfoxide（以下DMSO）で希釈後、試料としてアッセイに使用した。
Preparation of anti-tumor promoter activity test sample Take a part from the concentrated and dried sample, and dimethyl sulfoxide (DMSO) to make it 1000 times and 200 times the concentration of TPA (4 μg / ml). The sample was used for the assay as a sample.
Raji細胞培養液の調製
ダルべッコ変法イーグル培地26.96g、カナマイシン200mg、HEPES9.54gを殺菌水360mlに溶解して、無菌下0.22μmのフィルターでろ過滅菌した。これを5倍濃縮培養液として使用した。この5倍濃縮培養液40mlに殺菌水160ml、アンホテリシンB 0.2ml、7％重曹水6ml、牛胎児血清20mlを加え、これを10％FCS培地とし、Raji細胞の培養に使用した。
Preparation of Raji cell culture solution 26.96 g of Dulbecco's modified Eagle medium, 200 mg of kanamycin, and 9.54 g of HEPES were dissolved in 360 ml of sterilized water, and sterilized by filtration with a 0.22 μm filter under aseptic conditions. This was used as a 5-fold concentrated culture solution. To 40 ml of this 5-fold concentrated culture solution, 160 ml of sterilized water, 0.2 ml of amphotericin B, 6 ml of 7% sodium bicarbonate water, and 20 ml of fetal calf serum were added to form a 10% FCS medium, which was used for Raji cell culture.
抗ガン活性試験及び細胞毒性試験
生細胞数1.0×105個/mlに調製したRaji細胞懸濁液を1mlずつ分注し、各濃度に調製した試料10μl、0.1Mn-酪酸ナトリウム10μlを添加し、さらにTPA（4μg/ml）10μlを添加して5％CO2インキュベーターにて37℃で48時間培養した。その後、形態変化を観察し、生細胞数を数えた。また、コントロールとして、0.1Mn-酪酸ナトリウムとTPAのみを添加したものを指標として細胞の形態変化を観察した。また、n−酪酸ナトリウムのみを添加したものを同様に培養し48時間後の生細胞数をコントロールとして算出し、コントロールの生細胞数に対する供試試料における培養細胞の生育度合を、生細胞数の比で算出した。
Anti-cancer activity test and cytotoxicity test Dispense 1 ml of Raji cell suspension prepared to a viable cell count of 1.0 × 10 5 cells / ml, and add 10 μl of sample and 10 μl of 0.1 Mn-sodium butyrate to each concentration. Furthermore, 10 μl of TPA (4 μg / ml) was added and cultured at 37 ° C. for 48 hours in a 5% CO 2 incubator. Thereafter, morphological changes were observed and the number of viable cells was counted. In addition, as a control, changes in cell morphology were observed using as an index the addition of 0.1 Mn-sodium butyrate and TPA alone. In addition, culture with the addition of only sodium n-butyrate was performed in the same manner, and the number of viable cells after 48 hours was calculated as a control, and the degree of growth of the cultured cells in the test sample relative to the number of viable control cells was calculated as the number of living cells. Calculated as a ratio.
判定方法
5％CO2下、37℃の条件下で培養し、48時間後の細胞の変形を倒立顕微鏡で観察し、試料無添加のコントロールと比較し、1視野における抑制の強さを下記に示す方法にて5段階で判定した。
＋＋＋ 完全に抑制 （1視野に0−1個）
＋＋ 強く抑制 （1視野に2−3個）
＋ 適度に抑制 （1視野に5−6値）
−＋ 少し抑制 （コントロールと比べて差がある）
− 全く抑制しない （コントロールと比べて差がない）
また、細胞毒性試験では、培養48時間後に生育率（％）と生育度合（％）を調べた。
生育率＝（生細胞数／生細胞数＋死細胞数）×100（％）
生育度合＝（生細胞数／コントロールの生細胞数）×100（％）
Judgment method
Method of culturing under conditions of 37 ° C under 5% CO 2 and observing the deformation of cells 48 hours later with an inverted microscope. Judged in 5 stages.
+++ Completely suppressed (0-1 per field of view)
++ Strongly suppressed (2-3 per field of view)
+ Moderately suppressed (5-6 values per field of view)
-+ Slightly suppressed (difference compared to control)
-No suppression at all (no difference compared to control)
In the cytotoxicity test, the growth rate (%) and the degree of growth (%) were examined after 48 hours of culture.
Growth rate = (number of living cells / number of living cells + number of dead cells) × 100 (%)
Degree of growth = (number of living cells / number of living cells for control) x 100 (%)
［結果及び考察］
抗ガン活性試験及び細胞毒性試験
各抽出物の抗ガン活性を示した（表１）。ヤーコンのヘキサン抽出物（(1)、(4)、(7)、(10)、(13)）、アセトン抽出物（(2)、(5)、(8)、(11)、(14)）、70％MeOH抽出物（(3)、(6)、(9)、(12)、(15)）を、TPAの濃度に対して1000倍、及び200倍の濃度にDMSOにて希釈し、試料として活性試験に供した。葉の部分は、いずれの抽出溶媒においても強い活性がみられた。乾燥済みの皮の部分にも強い活性がみられたが、細胞毒性試験の結果より毒性が強いと考えられた。また、乾燥済みの芋を試料とした場合、生育率は約70％で、いずれの抽出溶媒においても活性がみられなかったが、他の部位においてはヘキサンが最も活性が強かった。これらの結果より、最適抽出溶媒はヘキサン、最適部位は葉であると考えられた。
[Results and discussion]
Anticancer activity test and cytotoxicity test The anticancer activity of each extract was shown (Table 1). Yacon hexane extract ((1), (4), (7), (10), (13)), acetone extract ((2), (5), (8), (11), (14) ), 70% MeOH extract ((3), (6), (9), (12), (15)) was diluted with DMSO to a concentration of 1000 and 200 times the concentration of TPA. The sample was subjected to an activity test. The leaf part showed strong activity in any extraction solvent. Although strong activity was also observed in the dried skin, it was considered to be more toxic than the result of the cytotoxicity test. When dried cocoons were used as samples, the growth rate was about 70%, and no activity was observed in any of the extraction solvents, but hexane was the most active in other sites. From these results, it was considered that the optimum extraction solvent was hexane and the optimum site was leaves.
（ヤーコンの抗ガン活性成分の単離）
実施例１の結果から、ヤーコンの葉（乾燥済み）には抗ガン活性成分が含まれていたことが分かった。また、抽出溶媒はヘキサンが最適であることも分かった。そこで本実施例では、ヤーコンの葉に含まれている抗ガン活性成分を明らかにするために、ヤーコンの葉から抗ガン活性成分を、カラムクロマトグラフィーと薄層クロマトグラフィーにより単離することにした。
(Isolation of anti-cancer active ingredient of Yacon)
From the results of Example 1, it was found that yacon leaves (dried) contained an anti-cancer active ingredient. It was also found that hexane is the optimum extraction solvent. Therefore, in this example, in order to clarify the anticancer active component contained in the yacon leaf, the anticancer active component was isolated from the yacon leaf by column chromatography and thin layer chromatography. .
［方法および結果］
試料の調製
ヤーコンの葉（FD乾燥済み）1.726kgをヘキサンで浸漬し、その後プレス機にてヘキサン可溶物質を抽出し、約15リットルの抽出液を得た。さらに濃縮乾固し、31.8gの乾固物を得た。
[Method and Result]
Preparation of samples 1.726 kg of Yacon leaves (FD dried) were immersed in hexane, and then hexane-soluble substances were extracted with a press machine to obtain about 15 liters of extract. The solution was further concentrated to dryness to obtain 31.8 g of a dried product.
カラムクロマトグラフィー
上記で調製した乾固物31.8gをヘキサン40mlに溶解し、シリカゲルカラム（250g、35cm×4.5cm）にのせた。ヘキサン-ジエチルエーテル系の溶出溶媒を順次流してFr.1〜Fr.8に分画し、それぞれの画分から一部をとり、TPAの濃度に対して200倍、50倍、及び20倍になるようにDMSOで希釈し試料とした後、これらを抗ガン活性試験に供した。（表２）
Fr．7−(1)、Fr．7−(2)、Fr．8では200倍、50倍ともに非常に強い活性がみられた。さらにFr．8においては、20倍でも非常に強い活性がみられた。これより、Fr．8に最も強い抗ガン活性成分が含まれていることが分かった。
Column chromatography 31.8 g of the dried product prepared above was dissolved in 40 ml of hexane and placed on a silica gel column (250 g, 35 cm × 4.5 cm). Elution solvent of hexane-diethyl ether system is sequentially flowed to fractionate into Fr.1 to Fr.8, and a part is taken from each fraction, and it becomes 200 times, 50 times, and 20 times the concentration of TPA. After diluting with DMSO to prepare samples, these were subjected to an anticancer activity test. (Table 2)
Fr. 7- (1), Fr. 7- (2), Fr. 8 showed very strong activity in both 200 and 50 times. Furthermore, Fr. In 8 the activity was very strong even 20 times. From this, Fr. 8 was found to contain the strongest anticancer active ingredient.
薄層クロマトグラフィー
上記で調製したFr.8から102.4mgをとり、これをアセトンに溶解し、ヘキサン-ジエチルエーテル系（1：4〜9）を展開溶媒として分取用シリカゲルプレート（20cm×20cm、0.5mm）で薄層クロマトグラフィーを行い、Fr.1-1′〜 Fr.1-8′に分画した。それぞれの画分から一部をとり、TPAの濃度に対して100倍、20倍、及び10倍になるようにDMSOにて希釈し、試料として活性試験に供した。
Fr.1-1′については再びヘキサン-ジエチルエーテル系溶媒で薄層クロマトグラフィーを行い、Fr.1-1″〜Fr.1-4″に分画した。
各画分の抗ガン活性を示した（表３）。特に、Fr．1-1′については100倍、20倍ともに活性が強く、生育率を見てもそれほど毒性がないと思われる。また、この画分を精製し抗ガン活性試験を供したところ、更に10倍でも強い活性を確認した。
Thin-layer chromatography Take 102.4 mg of Fr. 8 prepared above, dissolve it in acetone, and use a hexane-diethyl ether system (1: 4-9) as a developing solvent for a preparative silica gel plate (20 cm × 20 cm, 0.5 mm), and fractionated into Fr.1-1 ′ to Fr.1-8 ′. A part was taken from each fraction, diluted with DMSO so as to be 100 times, 20 times, and 10 times the concentration of TPA, and subjected to an activity test as a sample.
Fr.1-1 ′ was again subjected to thin layer chromatography with a hexane-diethyl ether solvent, and fractionated into Fr.1-1 ″ to Fr.1-4 ″.
The anticancer activity of each fraction was shown (Table 3). In particular, Fr. 1-1 'is 100 and 20 times more active, and the growth rate is not so toxic. Further, when this fraction was purified and subjected to an anticancer activity test, a strong activity was confirmed even 10 times.
（ヤーコンの抗ガン活性成分の構造解析）
実施例２からヤーコンから単離された成分は、強い抗ガン活性を示すことが分かった。そこで本実施例では、この抗ガン活性成分はどのような構造をしているのかを知るために、NMR分析を中心としてMSなど機器分析を行い、その構造解析を行った。また、NMR解析では、1H−1H COSY、COLOC、HMBC等の測定を行った。
(Structural analysis of Yacon anti-cancer active ingredient)
The component isolated from yacon from Example 2 was found to exhibit strong anti-cancer activity. Therefore, in this example, in order to know the structure of this anticancer active ingredient, instrumental analysis such as MS was performed focusing on NMR analysis, and the structural analysis was performed. In NMR analysis, 1H-1H COZY, COLOC, HMBC, and the like were measured.
［実験方法］
機器分析
上記で調製したFr．1−2”についてNMR解析及びMS分析を行った。
[experimental method]
Instrumental analysis Fr. NMR analysis and MS analysis were performed on 1-2 ″.
機器分析条件
〈NMR〉
装置：日本電子JNM-A400型核磁気共鳴装置
溶媒：Chloroform−d1，contains１％（v／v）TMS 99.8 atom ％D（Fr．1−1′）
Acetone−d6（Fr．1−2″）
標準物質：TMS（Tetramethylsilane）
周波数：400MHz
〈MS〉
装置：日本電子JMS−SX102AQQ Hydrid Mass Spectrometer
試料気化部温度：50℃→300℃（16℃／min．）
イオン化法：EI
イオン化電圧：70eV
標準物質：PFK（Perfluorokerosene）
Instrumental analysis conditions <NMR>
Equipment: JEOL JNM-A400 nuclear magnetic resonance system Solvent: Chloroform-d 1 , contains 1 % (v / v) TMS 99.8 atom% D (Fr. 1-1 ′)
Acetone−d 6 (Fr. 1-2 ″)
Reference material: TMS (Tetramethylsilane)
Frequency: 400MHz
<MS>
Equipment: JEOL JMS-SX102AQQ Hydrid Mass Spectrometer
Sample vaporization section temperature: 50 ° C → 300 ° C (16 ° C / min.)
Ionization method: EI
Ionization voltage: 70eV
Reference material: PFK (Perfluorokerosene)
［結果及び考察］
機器分析
Fr．1−2″についての13C−NMRスペクトルから炭素数23個、1H−NMRスペクトルからメチル基が数個、酸素を含むＯ−CH結合や、オレフィンのCHなどの存在が示唆された。
また、本物質の高分解能質量分析の結果、分子量464で、C23H28O10の元素組成であることが分かった。
次に、CHSHFスペクトルを用いて、すべての炭素上の水素との結合様式を明らかにした。次に、1H−1H COSYスペクトルから隣接した1H核相互の結合関係を明らかにした。
更に、COLOC、HMBC等により、遠距離の1H核と13C核の相関関係を明らかにしていった。本活性物質の平面構造は（図１）であることが明確になった。
最後に、立体構造を決定するため、NOESY測定を行った結果、立体構造を決定した。
単離した成分は、9-アセトキシ-10(2,3-ジメチル-オキシランカルボニルオキシ)-4メチル-12-メチレン-13-オキソ-3,14-ジオキサ-ロリシクロ[9.3.0.02,4］テトラデ-7-セン-8-カルボン酸メチルエステル（9-Acetoxy-10-(2,3-dimethyl-oxiranecarbonyloxy)-4-methyl-12-methylene-13-oxo-3,14-dioxa-tricyclo[9.3.0.02,4]tetradec-7-ene-8-carboxylic acid methyl ester]（図２）であった。
[Results and discussion]
Instrument analysis
Fr. The 13 C-NMR spectrum of 1-2 ″ indicated 23 carbon atoms, and the 1 H-NMR spectrum indicated several methyl groups. O-CH bonds containing oxygen, CH of olefins, and the like were suggested.
As a result of high-resolution mass spectrometry of this substance, it was found that it had a molecular weight of 464 and an elemental composition of C 23 H 28 O 10 .
Next, CHSHF spectra were used to clarify the mode of bonding with hydrogen on all carbons. Next, it revealed adjacent 1 H nuclei mutual coupling relation from 1 H- 1 H COZY spectrum.
Furthermore, the correlation between long-distance 1 H nuclei and 13 C nuclei was clarified by COLOC and HMBC. It became clear that the planar structure of the active substance was (FIG. 1).
Finally, NOESY measurement was performed to determine the three-dimensional structure, and as a result, the three-dimensional structure was determined.
The isolated component was 9-acetoxy-10 (2,3-dimethyl-oxiranecarbonyloxy) -4methyl-12-methylene-13-oxo-3,14-dioxa-loricyclo [9.3.0.0 2,4 ] tetrade -7-Sen-8-carboxylic acid methyl ester (9-Acetoxy-10- (2,3-dimethyl-oxiranecarbonyloxy) -4-methyl-12-methylene-13-oxo-3,14-dioxa-tricyclo [9.3. 0.02,4 ] tetradec-7-ene-8-carboxylic acid methyl ester] (FIG. 2).
本発明によって、安全性に問題がなく、安価で比較的容易に入手可能な材料（未利用材料であるヤーコンの芋皮および／または葉茎部）から、副作用が少ない、優れた抗ガン活性作用を有する組成物を提供すること、好ましくは発ガン活性作用を抑制すべき疾患を治療または予防するための組成物、より具体的には食品添加物、食品素材、飲食品、医薬品・医薬部外品および飼料からなる群から選ばれる形態のものを提供することが可能となる。 According to the present invention, an excellent anti-cancer activity with less side effects from a material that is safe and inexpensive and is relatively easily available (unused material, yak crust and / or leaf stem). A composition for treating or preventing a disease whose carcinogenic activity should be suppressed, more specifically, a food additive, a food material, a food or drink, a pharmaceutical product or a quasi-drug It becomes possible to provide the thing of the form chosen from the group which consists of goods and feed.
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