KR20170114140A - Composition for treating or preventing cancer comprising polyphenols of Artemisia annua - Google Patents
Composition for treating or preventing cancer comprising polyphenols of Artemisia annua Download PDFInfo
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- KR20170114140A KR20170114140A KR1020160041399A KR20160041399A KR20170114140A KR 20170114140 A KR20170114140 A KR 20170114140A KR 1020160041399 A KR1020160041399 A KR 1020160041399A KR 20160041399 A KR20160041399 A KR 20160041399A KR 20170114140 A KR20170114140 A KR 20170114140A
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- cancer
- glucoside
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- cells
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- 235000013824 polyphenols Nutrition 0.000 title claims abstract description 31
- 150000008442 polyphenolic compounds Chemical class 0.000 title claims abstract description 28
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- 240000000011 Artemisia annua Species 0.000 title claims abstract description 11
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
- A61K36/282—Artemisia, e.g. wormwood or sagebrush
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/308—Foods, ingredients or supplements having a functional effect on health having an effect on cancer prevention
Abstract
본 발명은 개똥쑥(Artemisia annua L.) 추출물로부터 분리된 폴리페놀 혼합물을 유효성분으로 함유하는, 암 예방 또는 치료용 조성물을 제공한다. The present invention provides a composition for preventing or treating cancer, which contains, as an active ingredient, a polyphenol mixture isolated from Artemisia annua L. extract.
Description
본 발명은 암 예방 또는 치료용 조성물에 관한 것으로서, 더 상세하게는 개똥쑥으로부터 분리된 폴리페놀을 유효성분으로 포함하는 암 예방 또는 치료용 조성물에 관한 것이다. TECHNICAL FIELD The present invention relates to a composition for preventing or treating cancer, and more particularly, to a composition for preventing or treating cancer, which comprises polyphenol isolated from dogwood mugwort as an effective ingredient.
의학의 발전과 함께, 노인 인구의 폭발적인 증가에 따라 노인 암환자 또한 증가할 것으로 예상되는 가운데 이러한 노인 인구에서 장기 저장(organ reservoir)의 부족으로 인해 치료 관련 사망이 증가하고 있고 전통적인 화학요법제의 사용으로 인한 심각한 부작용이 종종 발생하기도 한다. 게다가, 현대 화학요법제의 전략은 항암화학요법으로 치료하는 암환자의 삶의 질에 비중을 두고 있기 때문에 식이성 작용제(dietary agents)로서 심각한 독성없이 안전하게 항암 효과를 강화할 수 있는 피토케미컬(phytochemical)에 많은 관심이 집중되고 있다. 이러한 이유로 종래 잘 알려진 개똥쑥을 이용한 항암 효과를 나타내는 생리활성 물질 연구가 활발하게 진행되고 있다. 개똥쑥(Artemisia annua L.)은 국화과에 속하는 일년생 초본으로 열대 아시아 원산으로 우리나라를 비롯한 세계적으로 분포하고 있으며, 한방에서는 개똥쑥의 지상부를 해열제, 지혈제, 피부병 치료제, 살충제 등으로 사용하고 있다. 특히 개똥쑥의 주요 성분인 아테미시닌(artemisinin)과 그 유도체는 중국과 인도에서 열성 질환과 말라라아 치료제로 오래전부터 널리 사용되어 왔고 암세포에 대한 세포독성 효과를 갖고 있다. Along with the development of medicine, the elderly population is expected to increase with the explosion of the elderly population, and the lack of organ reservoir in these elderly population is leading to an increase in treatment-related deaths and the use of traditional chemotherapy Often resulting in serious side effects. In addition, the modern chemotherapy strategy focuses on the quality of life of cancer patients treated with chemotherapy, so dietary agents are phytochemicals that can safely enhance the anti-cancer effects without serious toxicity. There is much attention. For this reason, studies on physiologically active substances exhibiting anticancer effect using well-known mutant dog mugwort have been actively carried out. Artemisia annua L. is an annual herbaceous plant belonging to the Asteraceae family. It is distributed in Korea and other parts of the world. It is used as an antipyretic agent, hemostatic agent, treatment for skin diseases, insecticide and the like. Especially, artemisinin and its derivatives, which are the main components of mushroom, have long been used as a treatment for febrile diseases and malaria in China and India and have cytotoxic effects against cancer cells.
대한민국 공개특허 제2015-0087715호는 개똥쑥 추출물, 아테미시닌 또는 디히드로아테미시닌을 포함하는 간암의 예방 또는 치료용 조성물을 개시하고 있다. Korean Patent Laid-Open Publication No. 2015-0087715 discloses a composition for preventing or treating liver cancer including Artemisia sp. Extract, atemicinin or dihydroartemisinin.
그러나, 상기 선행기술의 경우, 충분한 유효성분 폴리페놀 혼합물 분석의 부재와 개똥쑥 추출물에서 분리한 조성물은 정상세포에서는 부작용이 없는 농도에서 암세포의 생육을 억제하기 위한 충분한 항암활성을 나타내지 않는 문제점이 있다. However, in the case of the prior art described above, there is a problem in that a sufficient amount of active ingredient polyphenol mixture analysis and a composition isolated from a dog mugwort extract do not exhibit sufficient anticancer activity to suppress the growth of cancer cells at a concentration at which there is no side effect in normal cells .
본 발명은 폴리폐놀만을 추출함으로써 상기와 같은 문제점을 포함하여 여러 문제점들을 해결하기 위한 것으로서, 보다 항암활성이 증가된 개똥쑥 성분을 유효성분으로 포함하는 암 예방 또는 치료용 조성물을 제공하는 것을 목적으로 한다. 그러나 이러한 과제는 예시적인 것으로, 이에 의해 본 발명의 범위가 한정되는 것은 아니다.The object of the present invention is to provide a composition for preventing or treating cancer, which comprises as an active ingredient a gallbladder gall bladder component having increased anticancer activity, to solve various problems including the above problems by extracting only polyphenol do. However, these problems are exemplary and do not limit the scope of the present invention.
본 발명의 일 관점에 따르면, 개똥쑥(Artemisia annua L.) 추출물로부터 분리된 폴리페놀 혼합물을 유효성분으로 함유하는, 암 예방 또는 치료용 조성물이 제공된다. According to one aspect of the present invention, there is provided a composition for preventing or treating cancer, which contains, as an active ingredient, a polyphenol mixture isolated from Artemisia annua L. extract.
본 발명의 다른 일 관점에 따르면, 개똥쑥(Artemisia annua L.) 추출물로부터 분리된 폴리페놀 화합물을 유효성분으로 함유하는, 암 예방 및 개선용 건강기능식품이 제공된다. According to another aspect of the present invention, there is provided a health functional food for cancer prevention and improvement, which contains, as an active ingredient, a polyphenol compound isolated from Artemisia annua L. extract.
상기한 바와 같이 이루어진 본 발명의 일 실시 예에 따르면, 개똥쑥으로부터 분리된 항암활성을 나타내는 유효성분을 포함하는 추출물을 이용하여 암 예방 또는 치료효과를 구현할 수 있다. 물론 이러한 효과에 의해 본 발명의 범위가 한정되는 것은 아니다. According to one embodiment of the present invention as described above, an effect of preventing or treating cancer can be realized by using an extract containing an active ingredient that exhibits anticancer activity isolated from dogwood mugwort. Of course, the scope of the present invention is not limited by these effects.
도 1은 개똥쑥 조직으로부터 유기용매를 이용하여 추출한 혼합물에서 HPLC-MS/MS 방법을 통해 다양한 종류의 폴리페놀을 확인한 그래프이다.
도 2는 본 발명의 개똥쑥 추출물 pKAL 처리에 따른 항암 효과를 관찰하기 위하여 인간 유방암 세포주(MDA-MB-231)와 인간 제대정맥 내피세포(ECs)의 세포 생존능을 분석한 그래프이다.
도 3은 본 발명의 개똥쑥 추출물 pKAL 처리에 따른 A549 폐암 세포의 생존능을 분석한 그래프이다.
도 4는 본 발명의 개똥쑥 추출물 pKAL 처리에 따른 A549 폐암 세포의 사멸을 확인한 사진이다.
도 5는 본 발명의 개똥쑥 추출물 pKAL 처리에 따른 U937 백혈병세포의 생존능을 분석한 그래프이다.
도 6은 본 발명의 개똥쑥 추출물 pKAL 처리에 따른 인간 유방암 세포주(MDA-MB-231)와 인간 제대정맥 내피세포(ECs)의 유착(adhesion) 분석한 사진(A)이고 그래프(B)이다.
도 7은 본 발명의 개똥쑥 추출물 pKAL 처리에 따른 인간 유방암 세포주(MDA-MB-231) 형태의 변화를 나타낸 메트리겔 침윤 분석 사진(A)이고 그래프(B)이다.
도 8은 본 발명의 개똥쑥 추출물 pKAL 처리에 따른 MMP-2 및 MMP-9의 발현을 확인하기 위한 젤라틴 자이모그래피 분석을 수행한 겔사진(A)이고 그래프(B)이다.
도 9는 본 발명의 개똥쑥 추출물 pKAL 처리에 따른 EMT-관련 단백질(Snail, β-catenin, N-cadherin 및 E-cadherin)의 발현을 확인한 웨스턴 블랏 겔 사진이다.
도 10은 본 발명의 개똥쑥 추출물 pKAL 처리에 따른 유착분자(VCAM-1 및 ICAM-1)의 발현을 확인한 웨스턴 블랏 겔사진과 그래프이다.
도 11은 본 발명의 개똥쑥 추출물 pKAL 처리에 따른 Akt 및 PKC 발현을 관찰한 웨스턴 블랏 겔사진이다.
도 12는 본 발명의 개똥쑥 추출물 pKAL 처리에 따른 A549 폐암 세포의 사멸을 관찰한 그래프이다.
도 13은 본 발명의 개똥쑥 추출물 pKAL 처리에 따른 세포사멸 유발인자의 발현을 관찰한 웨스턴 블랏 겔사진이다. FIG. 1 is a graph showing various kinds of polyphenols obtained by an HPLC-MS / MS method in a mixture extracted from an artificial wormwood tissue using an organic solvent.
FIG. 2 is a graph showing the cell viability of human breast cancer cell line (MDA-MB-231) and human umbilical vein endothelial cells (ECs) in order to observe the anticancer effect according to the treatment with the pKAL extract of the present invention.
FIG. 3 is a graph showing the survival ability of A549 lung cancer cells according to the pKAL treatment of Lauroginae japonica extract of the present invention.
FIG. 4 is a photograph showing the death of A549 lung cancer cells according to the pKAL treatment of the artichoke extract of the present invention.
FIG. 5 is a graph showing the viability of U937 leukemia cells according to the pKAL treatment of the present invention.
FIG. 6 is a photograph (A) and a graph (B) showing the adhesion of human breast cancer cell line (MDA-MB-231) and human umbilical vein endothelial cells (ECs) according to the pKAL treatment of the artichoke extract of the present invention.
FIG. 7 is a photograph (A) and a graph (B) of a metry gel infiltration analysis showing the change of the form of the human breast cancer cell line (MDA-MB-231) according to the pKAL treatment of the milk curcuma extract of the present invention.
FIG. 8 is a photograph (A) and a graph (B) of gelatin zymography analysis for confirming the expression of MMP-2 and MMP-9 according to the pKAL treatment of the artichoke extract of the present invention.
FIG. 9 is a photograph of a western blot gel showing the expression of EMT-related proteins (Snail, β-catenin, N-cadherin and E-cadherin) according to the pKAL treatment of the artichoke extract of the present invention.
10 is a Western blot gel photograph and a graph showing the expression of adhesion molecules (VCAM-1 and ICAM-1) according to the pKAL treatment of the rabbit extract of the present invention.
FIG. 11 is a photograph of western blot gel showing the expression of Akt and PKC according to the pKAL treatment of the artichoke extract of the present invention.
FIG. 12 is a graph showing the death of A549 lung cancer cells according to the pKAL treatment of the rabbit extract of the present invention.
FIG. 13 is a photograph of a western blot gel showing the expression of the apoptosis inducing factor according to the pKAL treatment of the rabbit extract of the present invention.
용어의 정의:Definition of Terms:
본 문서에서 사용되는 용어 "개똥쑥(Artemisia annua L. AA)"은 초롱꽃목 국화과의 한해살이 풀로 잔잎쑥ㅇ개땅쑥이라고도 한다. 높이 약 1m로 성장하며 길가나 빈터, 강가에서 자란다. 풀 전체에 털이 없고 특이한 냄새가 난고 줄기는 녹색으로 가지가 많이 갈라진다.As used herein, the term " Artemisia annua L. AA" is an annual plant of the Lycopodium Species. It grows up to about 1m in height and grows on roads, ponds and rivers. There are no hairs on the whole grass, it has a strange smell, and the stem is green with many branches.
본 문서에서 사용되는 용어 "상피간엽이행(epithelial??mesenchymal transition, EMT)"은 상피세포(epithelial cell)가 간엽세포(mesenchymal cell)의 모양과 특징으로 변화(간엽세포화)하는 현상으로 배아 발생, 상처 치유, 장기 섬유화, 암 전이에 중요한 기작이며 암 관련 상피간엽이행은 이동성과 침습성을 확보하기 위한 과정이면서 더 나아가, 상피 암세포의 대사 작용, 후성 유전, 분화에 있어 복잡하게 관여하는 포괄적인 리프로그래밍이 이루어지는 작업이라 할 수 있다. As used herein, the term "epithelial mesenchymal transition (EMT)" refers to a phenomenon in which epithelial cells are transformed into mesenchymal cells in shape and characteristics (mesenchymal cells) , Wound healing, long-term fibrosis, and cancer metastasis. Cancer-related epithelial mesenchymal transition is a process for securing mobility and invasiveness, as well as a comprehensive treatment of metaplasia, progeny, and differentiation of epithelial cancer cells This is the work of programming.
발명의 상세한 설명:DETAILED DESCRIPTION OF THE INVENTION [
본 발명의 일 관점에 따르면 개똥쑥(Artemisia annua L.) 추출물로부터 분리된 폴리페놀 혼합물을 유효성분으로 함유하는, 암 예방 또는 치료용 조성물이 제공된다. According to one aspect of the present invention, there is provided a composition for preventing or treating cancer, which comprises, as an active ingredient, a polyphenol mixture isolated from Artemisia annua L. extract.
상기 조성물에 있어서, 상기 개똥쑥 추출물은 C1 내지 C4의 저급 알콜, 주정 또는 이들의 혼합용매로 추출하여 제조될 수 있다. In the above composition, the ragweed extract may be prepared by extracting with C1 to C4 lower alcohol, alcohol, or a mixed solvent thereof.
상기 조성물에 있어서, 상기 폴리페놀 혼합물은 개똥쑥 조직을 파쇄하여 제조된 분말에 에탄올을 처리하여 추출하고 상기 추출물을 농축한 후 초산에틸로 추출함으로써 제조될 수 있고, 상기 초산에틸로 추출 과정은 2 내지 4회 반복될 수 있다. In the above composition, the polyphenol mixture may be prepared by treating ethanol with a powder prepared by shattering the artichoke tissue, concentrating the extract, and extracting with ethyl acetate. To 4 times.
상기 조성물에 있어서, 상기 폴리페놀 혼합물은 카페산(caffeic acid), 퀘르세틴-3-O-갈락토시드(quercetin-3-O-galactoside), 메아르세틴-글루코시드(mearnsetin-glucoside), 캠프테롤-3-O-글루코시드(kaempferol-3-O-glucoside), 퀘르세틴-3-O-글루코시드(quercetin-3-O-glucoside), 페룰산(ferulic acid), 이소람네틴-글루코시드(isorhamnetin-glucoside), 디오스메틴-7-O-D-글루코시드(diosmetin-7-O-D-glucoside), 루테올린-7-O-글루코시드(luteolin-7-O-glucoside), 퀘르세틴(quercetin), 퀘르세틴-3-O-메틸 에테르(quercetagetin-3-O-methyl ether), 루테올린(luteolin), 8-메톡시-캠프페롤(8-methoxy-kaempferol), 퀘르세타게틴-5,3-di-O-메틸 에테르(quercetagetin-5,3-di-O-methyl ether), 캠프페롤(kaempferol), 3,5-디히드록시-6,7,4'-트리메톡시플라본(3,5-dihydroxy-6,7,4'-trimethoxyflavone), 3,5-디히드록시-6,7,3',4'-테트라메톡시플라본(3,5-dihydroxy-6,7,3',4'-tetramethoxyflavone) 및 이소람네틴(isorhamnetin)을 포함할 수 있다.In the composition, the polyphenol mixture is selected from the group consisting of caffeic acid, quercetin-3-O-galactoside, mearnsetin-glucoside, Kaempferol-3-O-glucoside, quercetin-3-O-glucoside, ferulic acid, isorhamnetin-glucoside glucoside, diosmetin-7-OD-glucoside, luteolin-7-O-glucoside, quercetin, quercetin-3 Quercetagetin-3-O-methyl ether, luteolin, 8-methoxy-kaempferol, querceteggetin-5,3-di- Quercetagetin-5,3-di-O-methyl ether, kaempferol, 3,5-dihydroxy-6,7,4'-trimethoxy flavone , 7,4'-trimethoxyflavone), 3,5-dihydroxy-6,7,3 ', 4'-tetramethoxyflavone (3,5-dihydroxy-And isorhamnetin. ≪ / RTI >
상기 조성물에 있어서, 상기 암은 자궁경부암, 폐암, 췌장암, 비소세포성폐암, 간암, 결장암, 골암, 피부암, 두부암, 경부암, 피부 흑색종, 안구내 흑색종, 자궁암, 난소암, 직장암, 뇌종양, 방광암, 혈액암, 위암, 항문부근암, 유방암, 나팔관암종 또는 자궁내막암종일 수 있다. The composition according to
본 발명의 다른 일 관점에 따르면, 개똥쑥(Artemisia annua L.) 추출물로부터 분리된 폴리페놀 화합물을 유효성분으로 함유하는, 암 예방 및 개선용 건강기능식품이 제공된다. According to another aspect of the present invention, there is provided a health functional food for cancer prevention and improvement, which contains, as an active ingredient, a polyphenol compound isolated from Artemisia annua L. extract.
본 발명의 추출물을 포함하는 조성물은 통상의 방법에 따른 적절한 담체, 부형제 또는 희석제를 더 포함할 수 있다. 상기 담체, 부형제 및 희석제는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 또는 광물유 일 수 있다. 또한, 상기 조성물은 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 또는 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있고 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제등이 포함되며, 상기 부형제는 전분, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose), 락토오스(lactose), 젤라틴 등을 섞어 조제될 수 있다. The composition comprising the extract of the present invention may further comprise an appropriate carrier, excipient or diluent according to a conventional method. The carrier, the excipient and the diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose , Polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil. In addition, each of the above compositions may be formulated in the form of oral, granule, tablet, capsule, suspension, emulsion, syrup, aerosol or the like oral preparation, external preparation, suppository or sterilized injection solution according to a conventional method. In the case of formulation, it may be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, etc. which are usually used, and solid preparations for oral administration may contain tablets, pills, powders, granules, capsules And the excipient may be prepared by mixing starch, calcium carbonate, sucrose, lactose, gelatin, and the like.
본 발명의 추출물을 포함하는 조성물은 환자의 나이, 성별, 체중에 따라 달라질 수 있으나, 일반적으로 0.01 내지 500mg/㎏의 양, 바람직하게는 0.1 내지 100mg/㎏의 양을 일일 1회 내지 수회로 나누어 투여할 수 있고 투여량은 투여경로, 질병의 정도, 성별, 체중, 나이 등에 따라서 증감될 수 있으나 이에 한정된 것은 아니다. The composition containing the extract of the present invention may vary depending on the age, sex and body weight of the patient, but is generally administered in an amount of 0.01 to 500 mg / kg, preferably 0.1 to 100 mg / kg, And the dose may be increased or decreased depending on the route of administration, degree of disease, sex, weight, age, etc., but is not limited thereto.
본 발명의 추출물을 포함하는 조성물은 랫트, 마우스, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있고 임상 투여 시에 경구 또는 비경구로 투여가 가능하며 비경구 투여 시 복강내주사, 직장내주사, 피하주사, 정맥주사, 근육내주사, 자궁내 경막주사, 뇌혈관내 주사 또는 흉부내 주사에 의해 투여될 수 있고, 일반적인 의약품 제제의 형태로 사용될 수 있다The composition containing the extract of the present invention can be administered to mammals such as rats, mice, livestock, and humans in various routes, and can be administered orally or parenterally at the time of clinical administration. In parenteral administration, May be administered by injection, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, intracerebral injection or intrathoracic injection, and may be used in the form of a general pharmaceutical preparation
이하, 실시예를 통하여 본 발명을 더 상세히 설명한다. 그러나 본 발명은 이하에서 개시되는 실시예에 한정되는 것이 아니라 서로 다른 다양한 형태로 구현될 수 있는 것으로, 이하의 실시예는 본 발명의 개시가 완전하도록 하며, 통상의 지식을 가진 자에게 발명의 범주를 완전하게 알려주기 위해 제공되는 것이다. Hereinafter, the present invention will be described in more detail by way of examples. It should be understood, however, that the invention is not limited to the disclosed embodiments, but may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, Is provided to fully inform the user.
실시예 1: 폴리페놀 화합물 추출Example 1: Polyphenol compound extraction
본 발명의 일 실시예에 따라 한국 개똥쑥으로부터 폴리페놀 혼합물(polyphenol from Korean A. annua L, 이하, 'pKAL'이라 약칭함)을 추출하였다. According to one embodiment of the present invention, a polyphenol mixture (Korean pearl alae L , hereinafter abbreviated as "pKAL") was extracted from Korean white mugwort.
구체적으로, 개똥쑥 뿌리, 꽃, 잎 및 줄기가 포함된 개똥쑥(Korean A. annua L) 조직(100 g)을 파쇄하여 분말을 제조하였고 500 ml 70% 에탄올(ethanol)로 80℃에서 20시간 동안 추출하였다. 그 후, 고체를 여과하고 남은 용액을 100 ml로 농축한 후 초산 에틸(ethyl acetate) 200 ml을 가하여 잘 혼합한 후, 초산 에틸층을 회수하였다. 남은 물층에 대하여 연속으로 2회 초산 에틸 200 ml 추출을 한 후, 초산 에틸층을 혼합하여 용매를 증발시켜 초산 에틸 분획물을 제조하였다. 그런 다음 상기 초산 에틸 분획물에 대하여 종래의 HPLC-MS/MS 방법(Yun et al., Food Chem. Toxicol. 48: 903-909, 2010)을 적용하여 상기 폴리페놀 혼합물을 용출시켰다. 용출된 폴리페놀 혼합물은 약 81 mg 정도였고(수율 0.081%), 상기 폴리페놀 혼합물에 대하여 MS/MS 분석을 수행한 결과 총 19가지 종류의 폴리페놀을 검출할 수 있었으며, 이는 하기 표 1과 같다: Specifically, the powder was prepared by crushing 100 g of Korean A. annua L containing the root, flower, leaf and stems. The powder was prepared in 500 ml of 70% ethanol at 80 ° C for 20 hours Lt; / RTI > Thereafter, the solid was filtered, and the remaining solution was concentrated to 100 ml. 200 ml of ethyl acetate was added thereto, followed by thorough mixing, and then the ethyl acetate layer was recovered. The remaining water layer was extracted with 200 ml of ethyl acetate twice in succession, and then the ethyl acetate layer was mixed and the solvent was evaporated to prepare an ethyl acetate fraction. Then, the polyphenol mixture was eluted by applying a conventional HPLC-MS / MS method (Yun et al ., Food Chem. Toxicol. 48: 903-909, 2010) to the ethyl acetate fraction. As a result of MS / MS analysis of the polyphenol mixture, a total of 19 types of polyphenols could be detected, as shown in Table 1 below :
종래 개똥쑥으로부터 분리된 폴리페놀 혼합물에 포함된 폴리페놀과 본 실시예를 통해 분리된 폴리페놀은 모두 33 종류로 이는 하기와 같다:The polyphenols contained in the polyphenol mixture separated from the conventional artillery wormwood and the polyphenols separated through the present embodiment are 33 kinds, as follows:
카페산(caffeic acid, 1), 시링가알데하이드(syringic aldehyde, 2), 디카페올리니퀴닉산 이성질체(dicaffeoylquinic acid isomer, 3, 4, 11), 퀘르세틴 3-O- 갈락토시드(quercetin 3-O-galactoside, 5), 디카페올리니퀴닉산 이성질체(dicaffeoylquinic acid isomer, 6), 메안세틴3-O-헥소사이드 이성질체(mearnsetin 3-O-hexoside isomer, 7, 10), 캠퍼롤 3-O-글루코사이드(kaempferol 3-O-glucoside ,8), 퀘르세틴 3-O-글루코사이드(quercetin 3-O-glucoside, 9), 페룰산(ferulic acid, 12), 카페올리페룰올리니퀴닉산 이성질체(caffeoylferuloylquinic acid isomer, 13, 17-19), 이소람네틴 3-O-글루코시드(isorhamnetin 3-O-glucoside, 14), 디오스메틴 7-O-글루코사이드 (diosmetin 7-O-glucoside, 15), 루테올린 7-O-글루코사이드(luteolin 7-O-glucoside, 16), 디페룰올리니퀴닉산(diferuloylquinic acid, 21), 퀘르세틴(quercetin, 22), 디카페올리페룰올리니퀴닉산 이성질체(dicaffeoylferuloylquinic acid isomer, 23), 3-O-메틸퀘르세타게틴(3-O-methylquercetagetin, 24), 디카페올리페룰올리니퀴닉산 이성질체(dicaffeoylferuloylquinic acid isomer, 25), 루테올린(26), 8-메톡시캠퍼롤(8-methoxykaempferol, 27), 3,5-디메토시퀘르세타게틴(3,5-dimethoxyquercetagetin, 28), 카페올리디페룰올리니퀴닉산 (caffeoyldiferuloylquinic acid, 29), 캠퍼롤(kaempferol, 30), 3,5-디히드록시-6,7,4'-트리메토시플라본(3,5-dihydroxy-6,7,4'-trimethoxyflavone, 31), 3,5-디하이드록시-6,7,3',4'-테트라메토시플라본( 3,5-dihydroxy-6,7,3',4'-tetramethoxyflavone, 32) 및 이소람네틴(isorhamnetin, 33).(1), syringic aldehyde (2), dicaffeoylquinic acid isomer (3, 4, 11), quercetin 3-O -galactoside, 5), dicaffeoylquinic acid isomer (6), mearnsetin 3-O-hexoside isomer (7, 10), camperol 3-O-glucoside , kaempferol 3-O-glucoside (8), quercetin 3-O-glucoside (9), ferulic acid (12), caffeoylferuloylquinic acid isomer , 17-19), isorhamnetin 3-O-glucoside, 14, diosmetin 7-O-glucoside, 15, luteolin 7-O- Glucoside, luteolin 7-O-
상기 동정된 폴리페놀 중 퀘르세틴과 캠퍼롤 유도체는 총 폴리페놀의 84.8%를 차지하였고 12 종류의 히드록시신남산(hydroxycinnamic acids, 1, 3, 4, 6, 11, 13, 17??19, 21, 23 및 25)과 10종류의 플라보노이드(7, 9, 10, 14, 16, 22, 26, 및 30??32)는 종래 중국, 브라질 및 이탈리아 개똥쑥에서 동정되어 보고된 바 있으며 나머지 히드록시신남산과 플라보노이드는 본 실험의 개똥쑥 조직에서 처음으로 동정되었고 일부는 검출되지 않았다(도 1). 상기 추출한 폴리페놀 혼합물 내의 폴리페놀 함량을 하기 표 2에 표시하였다. Among the identified polyphenols, quercetin and camphorol derivatives accounted for 84.8% of the total polyphenols and 12 kinds of hydroxycinnamic acids (1, 3, 4, 6, 11, 13, 17, 19, 21 , 23 and 25) and 10 kinds of flavonoids (7, 9, 10, 14, 16, 22, 26, and 30 ?? 32) were previously identified and identified in Chinese, Brazilian, Cystine Namsan and flavonoids were identified for the first time in dog mugwort tissues of this experiment and some were not detected (Fig. 1). The polyphenol content in the extracted polyphenol mixture is shown in Table 2 below.
실시예 2: 세포배양 및 시약Example 2: Cell culture and reagent
본 발명의 인간 유방암 세포주(MDA-MB-231), 폐암 세포주(A549) 및 U937 백혈병세포주(leukemic cell)는 한국 세포주 은행 또는 ATCC에서 구매하였고 상기 세포주는 10% 우태아혈청(FBS, GIBCO BRL, Grand Island, NY, USA), 2 mM L-글루타민, 25 mM의 N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid, 25 mM NaHCO3, 100 IU/ml 페니실린 및 10 ㎍/ml 스트렙토마이신이 첨가된 RPMI 1640 배지에서 배양하였다. 또한 인간 제대정맥 내피세포(EA.hy 926 cells, EC)는 ATCC에서 구입하여 20% FBS, 2 mM L-글루타민, 5 U/ml 헤파린, 100 IU/ml 페니실린, 10 ㎍/ml 스트렙토마이신 및 50 ㎍/ml EC 성장 보조제(growth supplements)가 첨가된 199 배지(GIBCO BRL, Grand Island, NY, USA)에서 배양하였다. 그 후, 상기 세포들은 95% 가습 대기 환경과 5% CO2 조건으로 100 mm 배양접시에서 배양하였다. 아울러, VCAM-1, ICAM-1, Snail, N-cadherin, E-cadherin, Akt, PKC, p53, PARP, Caspase-3, cleaved Caspase-3, LC-3, Mcl-1, BAX 및 β-catenind에 대한 항체는 Santa Cruz 생명공학회사(Santa Cruz, CA, USA)로부터 구매하였고 phospho-Akt 및 phospho-PKC에 대한 항체는 Sigma-Aldrich Co.(St. Louis, MO, USA)에서 구매하였다. 또한, 재조합 종양괴사인자(TNF)는 R&D 시스템(Minneapolis, MN, USA)에서 구매하였고 Matrigel™ 기저막 매트릭스(basement membrane matrix)는 BD Biosciences(San Diego, CA, USA), 강화된 화학발광(enhanced chemiluminescence, ECL) 웨스턴 블랏 탐지 시약은 Amersham(Buckinghamshire, UK), β-액틴을 포함한 다른 모든 시약들은 Sigma-Aldrich (St, Louis, MO, USA)에서 구매하였다. The human breast cancer cell line (MDA-MB-231), the lung cancer cell line (A549) and the U937 leukemic cell line of the present invention were purchased from Korean Cell Line Bank or ATCC and the cell line was cultured with 10% fetal bovine serum (FBS, GIBCO BRL, Glutamine, 25 mM N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid, 25 mM NaHCO 3 , 100 IU / ml penicillin and 10 μg / ml streptomycin Gt; RPMI 1640 < / RTI > medium. Human umbilical vein endothelial cells (EA.hy 926 cells, EC) were purchased from ATCC and cultured in DMEM supplemented with 20% FBS, 2 mM L-glutamine, 5 U / ml heparin, 100 IU / ml penicillin, 10 ug / ml streptomycin and 50 (GIBCO BRL, Grand Island, NY, USA) supplemented with 10 μg / ml EC growth supplements. Then, the cells were cultured in 100 mm Petri dishes in 95% humidified air and 5% CO 2 environment conditions. In addition, VCAM-1, ICAM-1, Snail, N-cadherin, E-cadherin, Akt, PKC, p53, PARP, Caspase-3, cleaved Caspase-3, LC-3, Mcl- Antibodies to phospho-Akt and phospho-PKC were purchased from Sigma-Aldrich Co. (St. Louis, Mo., USA), purchased from Santa Cruz Biotechnology Company (Santa Cruz, CA, USA) Recombinant Tumor Necrosis Factor (TNF) was purchased from R & D Systems (Minneapolis, MN, USA) and Matrigel ™ basement membrane matrix was purchased from BD Biosciences (San Diego, CA, USA), enhanced chemiluminescence , ECL) Western blot detection reagents were purchased from Amersham (Buckinghamshire, UK) and all other reagents including β-actin were purchased from Sigma-Aldrich (St, Louis, MO, USA).
실시예 3: 세포 생존능 분석(MTT assay) Example 3: Cell viability assay (MTT assay)
본 발명의 일 실시예에 따라 pKAL 처리에 따른 인간 유방암 세포주(MDA-MB-231), 인간 제대정맥 내피세포(ECs), 폐암 세포주(A549) 및 U937 백혈병세포(leukemic cell)의 세포 생존능을 분석하였다. According to one embodiment of the present invention, cell viability of human breast cancer cell line (MDA-MB-231), human umbilical vein endothelial cell (ECs), lung cancer cell line (A549) and U937 leukemic cell according to pKAL treatment Respectively.
먼저, 인간 유방암 세포주(MDA-MB-231) 및 인간 제대정맥 내피세포(ECs)는24-웰 플레이트에 상기 세포를 웰당 104 세포를 파종하였고 pKAL을 1, 10, 50 및 100 ㎍/ml의 농도 조건으로 24시간 동안 처리하였다. 또한 폐암 세포주(A549)는 pKAL을 1, 5, 10 및 50 ㎍/ml의 농도 조건으로 24시간 및 48시간 동안 처리하였고 U937 백혈병세포(leukemic cell)는 pKAL을 1, 2, 5, 10, 20, 50 및 100 ㎍/ml의 농도 조건으로 24시간 및 48시간 동안 처리하였으며 5 mg/ml MTT 수용액 50 ㎕를 각 웰에 첨가하여 4시간 동안 배양하였다. 그 후, 상층액을 제거하고 포르마잔 결정(formazan crystals)을 각 웰에서 4 N HCl-isopropanol 200 ㎕를 이용하여 용해하였고 흡광도(absorbance)는 Infinite 200 microplate reader(TECAN Austria GmbH, Grㆆdig, Austria)를 이용하여 570 nm에서 측정하였다. 또한 A549 폐암 세포는 카메라(Nikon, DS-U3)가 장착된 올림푸스 현미경(CKX41)을 이용하여 이미지를 촬영하였다. First, human breast cancer cell line (MDA-MB-231) and human umbilical vein endothelial cells (ECs) were inoculated with 10 4 cells per well in a 24-well plate and pKAL was added at 1, 10, 50 and 100 μg / ml Lt; / RTI > for 24 hours. The lung cancer cell line (A549) was treated with pKAL at the concentrations of 1, 5, 10 and 50 ㎍ / ml for 24 and 48 hours. U937 leukemic cells were treated with pKAL at 1, 2, 5, , 50 and 100 μg / ml for 24 hours and 48 hours, and 50 μl of 5 mg / ml MTT aqueous solution was added to each well and cultured for 4 hours. The supernatant was then removed and formazan crystals were dissolved in 200 μl of 4 N HCl-isopropanol in each well. Absorbance was measured using an
그 결과, pKAL의 처리로 MDA-MB-231 유방암 세포의 생존능은 농도 의존적으로 억제되었으나 인간 제대정맥 내피세포(ECs)에서는 pKAL의 농도가 100 g/ml가 될 때 까지 생존능이 감소하지 않았다(도 2). 또한, A549 폐암 세포의 생존능은 pKAL의 처리에 따라 농도 의존적으로 억제되었고 pKAL의 용량 증가 시 세포사(cell death)를 유발하는 것을 확인하였다(도 3 및 4). 아울러, U937 백혈병세포(leukemic cell)에서도 농도 의존적으로 생존능이 억제되는 것을 확인하였다(도 5). 이러한 결과는 pKAL이 정상세포에서 최소 독성을 갖는 항암제로서 작용할 수 있는 암-특이적 독성을 가지고 있음을 말해준다. As a result, the viability of MDA-MB-231 breast cancer cells was inhibited by pKAL treatment in a concentration-dependent manner, but the survival of human umbilical vein endothelial cells (ECs) was not decreased until the pKAL concentration reached 100 g / ml 2). In addition, the survival capacity of A549 lung cancer cells was inhibited in a concentration-dependent manner by treatment with pKAL, and it was confirmed that cell death occurred when the dose of pKAL was increased (FIGS. 3 and 4). In addition, U937 leukemic cells were also found to be inhibited in a concentration dependent manner (FIG. 5). These results suggest that pKAL has cancer-specific toxicity that can act as an anticancer agent with minimal toxicity in normal cells.
실시예 4: 유착 분석(adhesion assay)Example 4: Adhesion assay
본 발명의 일 실시예에 따라 pKAL 처리에 따른 DA-MB-231 세포와 ECs의 유착 분석을 수행하였다. According to one embodiment of the present invention, adhesion analysis of DA-MB-231 cells and ECs according to pKAL treatment was performed.
구체적으로, ECs 및 MDA-MB-231 세포에 pKAL(1 - 30 ㎍/ml)를 24시간 동안 처리한 후 TNF(10 ng/ml)를 6시간동안 처리하였다. 이어서, 상기 처리된 MDA-MB-231 세포(7.5 X 105 세포/ml)를 37℃조건에서 상기 ECs에 첨가하였다. 30분경과 후, 세포 현탁액을 회수하고 상기 ECs는 PBS로 3회 세척하였으며 MDA-MB-231 세포는 광학현미경 하에서 계수하였고 카메라(Nikon, DS-U3)가 장착된 올림푸스 현미경(CKX41)을 이용하여 이미지를 촬영하였다. Specifically, ECs and MDA-MB-231 cells were treated with pKAL (1-30 μg / ml) for 24 hours and TNF (10 ng / ml) for 6 hours. The treated MDA-MB-231 cells (7.5 X 10 5 cells / ml) were then added to the ECs at 37 ° C. After 30 minutes, the cell suspension was recovered and the ECs were washed three times with PBS. MDA-MB-231 cells were counted under an optical microscope. Using an Olympus microscope (CKX41) equipped with a camera (Nikon, DS-U3) Images were taken.
그 결과, 대조군과 비교하여 ECs와 MDA-MB-231 유방암 세포의 유착이 6시간 TNF처리에 의해 급격하게 증가하였고(도 6A) ECs에 대한 TNF-유도 MDA-MB-231 유방암 세포의 유착은 항-유착효과를 가지고 있는 pKAL 처리에 의해 상당히 억제됨을 확인하였다(도 6B). 이러한 결과는 pKAL가 정상세포에 최소 독성을 가지고 있는 암전이(metastasis)를 억제하는 치료제로서 작용할 수 있음을 말해준다. As a result, the adhesion of ECs to MDA-MB-231 breast cancer cells was rapidly increased by treatment with 6 hours of TNF (Fig. 6A), compared with the control group, and adhesion of TNF-induced MDA-MB-231 breast cancer cells to ECs - < / RTI > adhesion by the pKAL treatment (FIG. 6B). These results suggest that pKAL may act as a therapeutic agent for suppressing metastasis, which has minimal toxicity to normal cells.
실시예 5: 매트리겔 침윤 분석(matrigel invasion assay)Example 5: Matrigel invasion assay < RTI ID = 0.0 >
본 발명의 일 실시예에 따라 pKAL 처리에 따른 MDA-MB-231 세포 형태의 변화를 메트리겔 침윤 분석을 통해 관찰하였다. In accordance with one embodiment of the present invention, changes in the morphology of MDA-MB-231 cells following pKAL treatment were observed through metry gel infiltration analysis.
구체적으로, pKAL(1 - 30 ㎍/ml)을 MDA-MB-231 세포에 1시간동안 전처리 후 TNF(10 ng/ml)를 6시간동안 처리하였고 현미경(×400)으로 세포 형태의 변화를 관찰하였다. 또한 상기 세포를 회수하여 매트리겔이 코팅된 삽입웰에 적용 후 37℃에서 16시간동안 배양하여 메트리겔 침윤 분석을 수행하였다. ECs는 pKAL을 24시간동안 전처리하고 PBS로 3회 세척하였고 TNF를 EC-코팅 매트리겔에 6시간동안 처리하였다. 또한 MDA-MB-231 세포를 EC-코팅 매트리겔 웰에 첨가하고 24시간 동안 배양하였고 비 침습세포(non-invasive cells)는 매트리겔 멤브레인을 제거한 상부에 방치하였다. 그 후, 매트리겔 막 하부의 세포를 4',6-diamino-2-phenylindole (DAPI)로 염색하였고 멤브레인을 통해 침습 세포의 수를 형광현미경을 이용하여 계수하였다. Specifically, pKAL (1 - 30 ㎍ / ml) was pretreated with MDA-MB-231 cells for 1 hour, treated with TNF (10 ng / ml) for 6 hours, and observed with a microscope Respectively. The cells were collected and applied to a matrigel coated insertion well, followed by culturing at 37 DEG C for 16 hours to perform metry gel infiltration analysis. ECs pretreated pKAL for 24 h, washed three times with PBS, and treated with ECF-coated matrigel for 6 h. MDA-MB-231 cells were also added to EC-coated Matrigel wells and cultured for 24 hours. Non-invasive cells were placed on top of the Matrigel membrane. Subsequently, cells underneath the Matrigel membrane were stained with 4 ', 6-diamino-2-phenylindole (DAPI) and the number of invading cells was counted using a fluorescence microscope through the membrane.
pKAL처리에 의한 스핀들(간엽)로부터 MDA-MB-231 세포의 형태적 변화를 관찰한 결과, 농도 의존적으로 라운드형(상피)을 형성하였다(도 7A). TNF에 의한 MDA-MB-231 세포 침습 활성화를 pKAL이 억제할 수 있는지 여부를 관찰한 결과, TNF는 농도 의존적으로 pKAL 처리에 의해 급격하게 억제된 암세포 침습을 상당히 증가시키는 것으로 나타났다(도 7B). 이러한 결과는 pKAL 처리가 EMT의 억제를 통해 암세포의 침습을 억제한다는 것을 의미한다. The morphological changes of MDA-MB-231 cells from the spindle (parenchyma) by pKAL treatment were observed to form round-shaped (epithelium) in a concentration-dependent manner (Fig. 7A). As a result of observing whether pKAL could inhibit the activation of MDA-MB-231 cell invasion by TNF, TNF significantly increased cancer cell invasion abruptly inhibited by pKAL treatment in a concentration-dependent manner (Fig. 7B). These results suggest that treatment with pKAL inhibits the invasion of cancer cells through inhibition of EMT.
실시예 6: 젤라틴 자이모그래피(gelatin zymography)Example 6: Gelatin zymography < RTI ID = 0.0 >
본 발명의 일 실시예에 따라 MMP-2(gelatinase-A) 및 MMP-9(gelatinase-B)의 발현을 확인하기 위해 젤라틴 자이모그래피 분석을 수행하였다. Gelatin assays were performed to confirm the expression of MMP-2 (gelatinase-A) and MMP-9 (gelatinase-B) according to an embodiment of the present invention.
구체적으로, MDA-MB-231 세포를 5 × 104 cells/ml의 농도로 파종하였고 pKAL를 1시간 동안 전처리한 후 TNF(10 ng/ml)를 12시간 동안 추가적으로 처리하였다. 또한 배양 배지에서 분비된 MMP-2 및 MMP-9에 대한 젤라틴용해성 활성(gelatinolytic activities)은 4℃에서 젤라틴(1 mg/ml)을 포함하는 8% 폴리아크릴아미드 겔을 이용한 전기영동으로 측정하였고 배양액은 피어스 단백질 농축기 7 ml/9K, MWCO 장비(Thermo, Pierce, Rockford, IL, USA)를 이용하여 농축하였으며 배지 내 단백질은 80% 알코올 아세톤으로 침전시킨 후 샘플 버퍼(0.03% 브롬페놀 블루, 0.4 M Tris-HCl pH 7.4, 20% 글리세롤 및 5% SDS)와 혼합하였으며 젤라틴이 포함된 8% SDS-폴리아크릴아마이드 겔을 이용하여 분리하였다. 이어서, 상기 겔을 재생 버퍼(renaturing buffer, 2.5% Triton X-100)로 1시간 동안 세척한 후, 발현 버퍼(developing buffer, 50 mM Tris, 20 mM NaCl, 5 mM CaCl2, 0.02% Brij35, pH 7.5)에서 37℃조건으로 24시간 동안 배양하였다. 그 후 상기 겔을 0.05% 코마시 브릴리언트 블루 R-250로 염색하였고 50% 메탄올 및 10% 아세트산으로 탈색(destained)하였으며 코마시 브릴리언트 블루 염색으로 젤라틴 분해(gelatin degradation)를 나타내는 흰색 용해 영역(white lysis zones)을 확인하였다. Specifically, MDA-MB-231 cells were inoculated at a density of 5 × 10 4 cells / ml, pretreated with pKAL for 1 hour, and then treated with TNF (10 ng / ml) for 12 hours. The gelatinolytic activities of MMP-2 and MMP-9 secreted from the culture medium were measured by electrophoresis using 8% polyacrylamide gel containing gelatin (1 mg / ml) at 4 ° C, (0.03% Bromophenol Blue, 0.4 M) was added to the culture medium after precipitation with 80% alcohol acetone, and the protein was concentrated using a Pierce Protein Concentrator (7 ml / 9K, MWCO instrument, Thermo, Pierce, Rockford, IL, USA) Tris-HCl pH 7.4, 20% glycerol and 5% SDS) and separated using an 8% SDS-polyacrylamide gel containing gelatin. Then, the gel was washed with a renaturing buffer (2.5% Triton X-100) for 1 hour and then developed with a developing buffer (50 mM Tris, 20 mM NaCl, 5 mM CaCl 2 , 0.02
그 결과, pKAL의 처리는 분비된 MMPs(matrix metalloproteinases)의 발현을 억제하는 것으로 나타났다(도 8). As a result, treatment with pKAL inhibited the expression of secreted MMPs (matrix metalloproteinases) (Fig. 8).
실시예 7: 웨스턴 블랏 분석Example 7: Western blot analysis
본 발명의 일 실시예에 따라 MDA-MB-231 유방암 세포 및 ECs에 pKAL 처리에 따른 EMT-관련 단백질(Snail, β-catenin, N-cadherin 및 E-cadherin)의 발현과 유착분자(VCAM-1 및 ICAM-1)의 발현을 관찰하기 위해 웨스턴 블랏 분석을 수행하였다. Expression of EMT-related proteins (Snail, β-catenin, N-cadherin and E-cadherin) and adhesion molecules (VCAM-1 ≪ / RTI > and ICAM-1).
구체적으로, MDA-MB-231 유방암 세포는 pKAL(1 - 30 ㎍/ml)을 6시간동안 처리하였고 MDA-MB-231 유방암 세포 또는 ECs에 pKAL을 1시간 처리 후 TNF(10 ng/ml)를 6시간동안 처리하였다. 그 후, 상기 세포를 PRO-PREP 단백질 추출 수용액(iNtRON Biotechnology, Seoul, Korea)을 이용하여 용해시켰고 조건 배양액(conditioned media, CM)의 단백질은 피어스 농축기 7 ml/9K, MWCO 장비(Thermo, Pierce, Rockford, IL, USA)를 이용하여 20배 농축하였다. 상기 농축된 단백질은 BioRad 단백질 분석(BioRad Lab., Hercules, CA, USA)으로 정량화하였고 상기 단백질의 50 ㎍ 부분 표본을 이용하여 7.5-12.5% 도데실황산나트륨 폴리아크릴아마이드 겔 전기영동을 수행하였으며 Hybond-P+ 폴리비닐리덴 다이플루오라이드 멤브레인(Amersham Biosciences UK Ltd)으로 전이하였다. 상기 멤브레인은 2차 항체가 결합된 고추냉이 퍼옥시다아제를 처리한 후 지정된 1차 항체와 함께 배양하였고 ECL 검측 시스템을 이용하여 블랏(blot)을 확인하였으며 β-액틴은 대조군 단백질(loading control)로 사용하였다. Specifically, MDA-MB-231 breast cancer cells were treated with pKAL (1-30 μg / ml) for 6 hours and treated with MDA-MB-231 breast cancer cells or ECs for 1 hour with pKAL (10 ng / ml) For 6 hours. Then, the cells were lysed using PRO-PREP protein extraction aqueous solution (iNtRON Biotechnology, Seoul, Korea) and proteins of conditioned media (CM) were collected by using Pierce concentrator 7 ml / 9K, MWCO equipment (Thermo, Pierce, Rockford, IL, USA). The concentrated protein was quantitated with BioRad protein analysis (BioRad Lab., Hercules, Calif., USA) and 7.5-12.5% sodium dodecyl sulfate polyacrylamide gel electrophoresis was performed using a 50 부분 aliquot of the protein. Hybond- P + polyvinylidene difluoride membrane (Amersham Biosciences UK Ltd). The membrane was incubated with the primary antibody after treatment with a secondary antibody-conjugated horseradish peroxidase, blotted using an ECL detection system, and β-actin was used as a control protein (loading control) Respectively.
그 결과, pKAL의 처리에 간엽 마커(mesenchymal markers)인 Snail과 N-cadherin의 발현은 급격하게 감소하였으나 β-catenin 및 E-cadherin의 발현은 감소하지 않은 것으로 나타났다(도 9). 이러한 결과는 pKAL의 처리가 간엽 마커 특히, N-cadherin의 하향조절로 인해 EMT(epithelial-mesenchymal transition)를 억제하는 것을 의미한다. 또한, pKAL의 처리는 유착분자인 VCAM-1의 발현을 급격하게 억제하였으나 ICAM-1의 발현은 억제하지 못하는 것으로 나타났고(도 10A), TNF-유도 VCAM-1의 발현을 상당히 억제하였으나 MDA-MB-231 세포 및 ECs에서 TNF-유도 ICAM-1의 발현은 억제하지 못하는 것으로 나타났다(도 10B 및 10C). 이러한 결과는 pKAL가 암세포와 ECs에서 VCAM-1의 발현을 감소시키는 항-유착 효과가 있음을 말해준다. As a result, the expressions of Snail and N-cadherin, which are mesenchymal markers, were drastically decreased in the treatment of pKAL, but the expression of β-catenin and E-cadherin was not decreased (FIG. 9). These results indicate that the treatment of pKAL suppresses the epithelial-mesenchymal transition (EMT) due to the down-regulation of the hepatic markers, especially N-cadherin. In addition, treatment with pKAL abruptly suppressed the expression of the adhesion molecule VCAM-1, but did not inhibit the expression of ICAM-1 (Fig. 10A), and significantly suppressed the expression of TNF-induced VCAM- But not TNF-induced ICAM-1 expression in MB-231 cells and ECs (FIGS. 10B and 10C). These results suggest that pKAL has an anti-adhesion effect that reduces the expression of VCAM-1 in cancer cells and ECs.
실시예 8: Akt 및 PKC 발현 Example 8: Akt and PKC expression
본 발명의 일 실시예에 따라 pKAL 처리에 따른 상류 신호전달 경로(upstream signaling pathways)를 연구하기 위해 Akt 및 PKC 발현을 관찰하였다. 구체적으로, pKAL를 MDA-MB-231 세포 및 ECs에 1시간 동안 전처리 하고 TNF를 6시간 동안 처리하였다. 그 후 전체 세포 용해물(whole-cell lysate) 30 ㎍을 이용하여 phospho-Akt, Akt, phospho-PKC, PKC, N-cadherin 및 E-cadherin의 발현을 웨스턴 블랏 분석을 통해 확인하였다. In order to investigate upstream signaling pathways following pKAL treatment, Akt and PKC expression were observed in accordance with one embodiment of the present invention. Specifically, pKAL was pretreated with MDA-MB-231 cells and ECs for 1 hour and treated with TNF for 6 hours. The expression of phospho-Akt, Akt, phospho-PKC, PKC, N-cadherin and E-cadherin was confirmed by Western blot analysis using 30 ㎍ of whole cell lysate.
그 결과, pKAL의 처리에 의해 Akt의 인산화는 농도 의존적으로 억제되었으나 PKC의 인산화는 농도 의존적으로 증가되었고(도 11A) pKAL의 처리 후 TNF에 의해 활성화된 MDA-MB-231 세포 및 ECs에서의 p-Akt 및 p-PKC 발현을 관찰한 결과, TNF의 처리는 MDA-MB-231세포에서 Akt의 인산화를 급격하게 증가시켰으나 PKC의 인산화를 억제하는 것으로 나타났다(도 11B). 그러나 ECs에서 TNF의 처리는 Akt 및 PKC의 인산화를 급격하게 증가시켰고 pKAL의 처리는 Akt의 인산화를 억제시켰으나 PKC의 인산화는 억제시키지 못하는 것으로 나타났다(도 11C). 따라서 Akt 전달경로는 pKAL-유도 항암 효과와 관련된 주요 상류 신호전달 경로로서의 역할을 한다는 것을 의미한다. As a result, the phosphorylation of Akt was inhibited in a concentration-dependent manner by treatment with pKAL, but phosphorylation of PKC was increased in a concentration-dependent manner (Fig. 11A) -Akt and p-PKC expression, TNF treatment significantly increased phosphorylation of Akt in MDA-MB-231 cells but inhibited phosphorylation of PKC (Fig. 11B). However, the treatment of TNF in ECs dramatically increased the phosphorylation of Akt and PKC, and the treatment of pKAL inhibited phosphorylation of Akt but did not inhibit phosphorylation of PKC (Fig. 11C). Thus, the Akt translocation pathway serves as a key upstream signaling pathway involved in the pKAL-induced anticancer effect.
실시예 9: 세포사멸 유발Example 9: induction of apoptosis
본 발명의 일 실시예에 따라 pKAL의 처리에 따른 A549 폐암 세포의 사멸을 확인하였다. 먼저, A549 폐암 세포에 pKAL(10 ㎍/ml)을 48시간 동안 처리한 후 PBS로 3회 세척하였으며 상기 세포를 Annexin V-PI 이중 염색(double staining) 후 유세포분석기(flow cytometry)로 측정하였다. 또한 세포사멸 유발 검증 및 기전을 확인하기 위하여 A549 폐암 세포에 pKAL(1, 5, 10 및 50 ㎍/ml)을 24시간 처리하고 웨스턴 블랏 분석을 통해 세포사멸 유발인자(p53, PARP, Caspase-3, cleaved Caspase-3, LC-3, Mcl-1, BAX)의 발현을 관찰하였다. In accordance with one embodiment of the present invention, the death of A549 lung cancer cells following treatment with pKAL was confirmed. First, A549 lung cancer cells were treated with pKAL (10 μg / ml) for 48 hours, washed three times with PBS, and the cells were subjected to double staining with Annexin V-PI followed by flow cytometry. To confirm the apoptosis induction and the mechanism of apoptosis, A549 lung cancer cells were treated with pKAL (1, 5, 10 and 50 ㎍ / ml) for 24 hours and Western blot analysis was performed to determine apoptosis inducing factors (p53, PARP, Caspase-3 , cleaved Caspase-3, LC-3, Mcl-1, and BAX).
그 결과, pKAL의 처리시간이 증가함에 따라 A549 폐암 세포의 사멸이 증가하는 것으로 나타났고(도 12) 세포사멸 유발인자의 발현은 pKAL의 처리에 따라 농도 의존적으로 상향 조절되면 억제인자는 하향 조절되는 것을 확인하였다(도 13). As a result, the death of A549 lung cancer cells was increased as the treatment time of pKAL was increased (Fig. 12), and the expression of apoptosis inducer was up-regulated depending on treatment with pKAL, and the inhibitory factor was down-regulated (Fig. 13).
본 발명은 상술한 실시 예를 참고로 설명되었으나 이는 예시적인 것에 불과하며, 당해 기술 분야에서 통상의 지식을 가진 자라면 이로부터 다양한 변형 및 균등한 다른 실시예가 가능하다는 점을 이해할 것이다. 따라서 본 발명의 진정한 기술적 보호 범위는 첨부된 특허청구범위의 기술적 사상에 의하여 정해져야 할 것이다.While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the invention is not limited to the disclosed embodiments, but, on the contrary, is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims. Accordingly, the true scope of the present invention should be determined by the technical idea of the appended claims.
Claims (6)
상기 개똥쑥 추출물은 C1 내지 C4의 저급 알콜, 주정 또는 이들의 혼합용매로 추출하여 제조되는 것을 특징으로 하는, 암 예방 또는 치료용 조성물.The method according to claim 1,
The composition for prevention or treatment of cancer, which is prepared by extracting Lauroginae Extract with a lower alcohol of C1 to C4, a alcohol, or a mixed solvent thereof.
상기 폴리페놀 혼합물은 개똥쑥 조직을 파쇄하여 제조된 분말에 에탄올을 처리하여 추출하고 상기 추출물을 농축한 후 초산에틸로 추출하여 제조되는, 암 예방 또는 치료용 조성물.The method according to claim 1,
Wherein the polyphenol mixture is prepared by treating ethanol with a powder prepared by disrupting the artichoke tissue, concentrating the extract, and extracting with ethyl acetate.
상기 폴리페놀 혼합물은 카페산(caffeic acid), 퀘르세틴-3-O-갈락토시드(quercetin-3-O-galactoside), 메아르세틴-글루코시드(mearnsetin-glucoside), 캠프테롤-3-O-글루코시드(kaempferol-3-O-glucoside), 퀘르세틴-3-O-글루코시드(quercetin-3-O-glucoside), 페룰산(ferulic acid), 이소람네틴-글루코시드(isorhamnetin-glucoside), 디오스메틴-7-O-D-글루코시드(diosmetin-7-O-D-glucoside), 루테올린-7-O-글루코시드(luteolin-7-O-glucoside), 퀘르세틴(quercetin), 퀘르세틴-3-O-메틸 에테르(quercetagetin-3-O-methyl ether), 루테올린(luteolin), 8-메톡시-캠프페롤(8-methoxy-kaempferol), 퀘르세타게틴-5,3-di-O-메틸 에테르(quercetagetin-5,3-di-O-methyl ether), 캠프페롤(kaempferol), 3,5-디히드록시-6,7,4'-트리메톡시플라본(3,5-dihydroxy-6,7,4'-trimethoxyflavone), 3,5-디히드록시-6,7,3',4'-테트라메톡시플라본(3,5-dihydroxy-6,7,3',4'-tetramethoxyflavone) 및 이소람네틴(isorhamnetin)을 포함하는, 암 예방 또는 치료용 조성물.The method according to claim 1,
Wherein said polyphenol mixture is selected from the group consisting of caffeic acid, quercetin-3-O-galactoside, mearnsetin-glucoside, campesterol- Glucoside, kaempferol-3-O-glucoside, quercetin-3-O-glucoside, ferulic acid, isorhamnetin-glucoside, 7-OD-glucoside, luteolin-7-O-glucoside, quercetin, quercetin-3-O-methyl ether quercetagetin-3-O-methyl ether, luteolin, 8-methoxy-kaempferol, quercetagetin- 5,3-di-O-methyl ether, kaempferol, 3,5-dihydroxy-6,7,4'-trimethoxy flavone, 3,5-dihydroxy-6,7,3 ', 4 ' -tetramethoxyflavone), 3,5-dihydroxy- isorhamnetin) Containing composition for preventing or treating cancer.
상기 암은 자궁경부암, 폐암, 췌장암, 비소세포성폐암, 간암, 결장암, 골암, 피부암, 두부암, 경부암, 피부 흑색종, 안구내 흑색종, 자궁암, 난소암, 직장암, 뇌종양, 방광암, 혈액암, 위암, 항문부근암, 유방암, 나팔관암종 또는 자궁내막암종인, 암 예방 또는 치료용 조성물.The method according to claim 1,
The cancer is selected from the group consisting of cervical cancer, lung cancer, pancreatic cancer, non-small cell lung cancer, liver cancer, colon cancer, bone cancer, skin cancer, head cancer, cervical cancer, skin melanoma, intrabranchial melanoma, uterine cancer, ovarian cancer, , Gastric cancer, perianal cancer, breast cancer, fallopian tube carcinoma, or endometrial carcinoma.
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