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1 大田大學校韓醫學硏究所論文集 145 第 19 卷第 2 號 2011 年 2 月 20 日 인삼의항암작용에대한한의학관련논문분석 장성일 1 유화승 1 * 1) Oriental Medicine papers review on Anticancer Effect of Ginseng Jang Sung-Il 1 Yoo Hwa-Seung 1 * * 1 East-West Cancer Center, Dunsan Oriental Hospital of Daejeon University Backgrounds: Multidisciplinary approaches including surgery, chemotherapy, and radiation therapy are currently being performed to target various cancers in Western Medicine. However, some cancers still remain difficult to battle, which has long attracted many scientists for the discovery of new agents to fight cancers. Ginseng is one of the herbs used in Oriental Medicine including Korea, China and Japan. We have further investigated ginseng for its anticancer effect. Objective: This is a comprehensive review summary of anticancer effect of ginseng and ginsenoids as a possible agent for future cancer treatment. Methods: Data were retrieved from two web sites; and and authorized texts concerning anticancer effects of ginseng. From collected data, information on anticancer effect of ginseng was thoroughly sorted, restructured, then assessed. Results: Panax Ginseng C.A. Meyer belongs to Araliaceae Panax family, a perennial prairie plant with its root known as Ginseng Radix. Ginseng induces anticancer effect through cell cycle arrest, acceleration of apoptosis, anti-angiogenesis, and suppression of metastasis. Anticancer effect of ginseng may be due to single compound or multi-compound actions. Many studies report involvement of immune mechanisms of cytokines, Natural Killer (NK) cells, macrophages and some antibodies in enhancing anticancer effect of ginseng. In near future, possibility of applying these mechanisms into clinical trials is convinced. There were some important findings on saponin in ginsenoids in reviewing for this article; First, eradication of metastatic tumors were influenced by macrophage activation. Second, suppression of malignant melanoma cell metastasis to lung were induced by macrophage and NK cell activation in spleen with red ginseng acidic polysaccharide (RGAP). Third, final metabolites of M1, M4 had exerted anticancer effect of ginseng. Conclusion: Unknown anticancer mechanisms of ginseng have been studied for many years up until now. Ginseng is comprised of multiple bio-chemical compounds that create complex pharmaceutical interactions. Therefore, for its proper usage and safe prescription, studies on different types of ginseng and patients susceptibility to ginseng according to their constitution and stages of the disease should be further pursued. More efforts are needed to understand the anticancer mechanisms of ginseng as well. Key words: ginseng; Panax; cancer Ⅰ. 서론 * 교신저자 : 유화승, 대전대학교둔산한방병원동서암센터 altyhs@dju.kr 접수일 : 2010 년 11 월 22 일게재확정일 : 2011 년 2 월 8 일

2 146 大田大學校韓醫學硏究所論文集第 19 卷第 2 號 2008년기준한국인사망률 1위암은인구 10 만명당 139.5명이며암사망자는폐암 (13.9명), 간암 (22.9명), 위암 (20.9명), 대장암 (13.9명), 췌장암 (7.6명), 유방암 (3.5명), 백혈병 (3.1명), 식도암 (2.8명) 순이었다. 1) 현재서양의학에서암치료법은외과적수술요법, 방사선요법, 화학적약물요법등을시행하고있다. 특히약물요법에서시행하는항암제의장점도있지만암환자의입장에서그에따른여러가지부작용의피해또한심각한면이많다. 그로인해세포독성과암세포의괴사, 약물요법의치료율증가또한면역증강이라는여러장점을가진새로운약물에대한많은연구가이루어지고있다. 2-3) 예로부터한의학에서약물을이용한질병치료에많은경험을가지고있지만구체적인기전과표준화대한연구는규명중인상태로있다. 그중에서도인삼은한의학에서오랫동안사용되고있으며여러연구를통해많은효능을갖고있는것으로알려져있지만특히항암작용에대한여러가지효능이점점나타나고있다. 이에저자는인삼의항암작용기전과효과에대한현재까지연구결과를소개하여현재의연구진행상황을고찰하고자한다. Ⅱ. 연구방법 1) 자료수집방법자료수집방법으로는 과 에서관련논문을검색한결과를토대로전자파일을다운받거나각도서관및학회에의뢰, 원문복사를하는방법으로자료를수집하였다. 이외에도단행본으로출간된서적중관련서적을구입하여필요한범위를요약, 발췌하였다. 2) 자료수집범위논문은인삼의항암효능에관련된임상보고, 고찰논문등과질병, 증후의치료효과를입증한국내외논문들을참조하였다. 단행본은권위를 인정받는교과서를위주로수집하였고, 이외인삼에관련된서적을추가로수집하였다. Ⅲ. 결과 인삼은오갈피나무과 (ARaliaceae) 인삼속 (Panax) 에속하는다년생초본류로서한의학에서는그뿌리를인삼 (Ginseng Radix) 이라한다. 지구의북반구, 특히히말라야, 중국, 일본, 한국, 북미에서발견되는식물이며자생지역에따라 ginseng C.A. Meyer,japonicus C.A.Meyer,major Ting, notoginseng(burkil)f.h.chen,omeiensis J.Wen,pseudoginseng Wallich,quinquefolius L,sinensis J.Wen,stipuleanatus H.T.Tasi & K.M.Feng,trifolius L,wangianus Sun, zingiberensis C.Y.Wu & K.M.Feng 등의 12가지종류로나눌수있다. 4) 인삼은사포닌성분과비사포닌성분으로나눌수있으며, 현재 ginsenoside 라고부르는사포닌글리코사이드가활동성이크다. 이것은 protopanaxadol 계, protopanaxtriol 계, oleanolic 계로나누어진다. 현재약 34종의 ginsenoside 가수삼, 백삼, 홍삼에서추출되었는데이들을 Thin Layer Chromatography (TLC) 에서의극성순서에따라 ginsenoside-rx 라명하였다. ginsenoside 외에 polyacetylenes,phenols,sesquiterpenes,alkaloi ds,polysaccharides,oligosaccharides,oligopept ides,aminoglycosides등의비사포닌성분도포함되어있으며, 최근이성분들이항산화작용, 항암작용, 항당뇨작용, 면역억제작용, 항보체작용등을하는것으로보고된바있다. 5) 현재까지인삼의연구는각종추출물, 사포닌류, 진세노사이드분획물, 중성또는산성다당체, 단백질성분, 에탄올불용성분획물, polyacetylene 성분, 조직배양체등이여러면역계에나타나는반응들로진행되고있다. 6) 항암작용의기전에대한연구는암진행을예방하며세포사멸촉진, 신생혈관억제촉진, 재발방지, 전이억제등을포함하여암세포성장주기를차단하는것등을포함한다. 7)

3 인삼의항암작용에대한한의학관련논문분석 147 Natural Killer cell (NK cell) 은동물실험과시험관실험에서암세포를죽일수있고인체를암으로부터지켜주는중요한방어역할을한다. Ginseng acidic polysaccharide (RGAP) 는 ovariectomized rat에서 NK 세포의종양세포치사활성을증가시켰고, NK 세포활성조절에대한상승효과를보였다. 8) 다수의연구에서는인삼의여러성분은 NK 세포의활성화에의해매개되는면역조절자로역할하여항암 항염작용을나타낼수있다고보고하고있다. 9-17) 김등은 dendritic cell (DC) 은성숙하면포식한항원을 T세포에제시하고항원을제시받은 T 세포는분열 증식은물론 interleukin-2 (IL-2). Interferon- (IFN- ) 와같은 cytokine을분비함으로써면역반응을유도하는데홍삼사포닌은 DC의성숙을유도한다고밝혔다. 홍삼시료를처리한 DC와함께배양한 allogeneic T세포의증식을유도하였고, syngeneic T세포인 CD4+ 세포와 CD8+ 세포의증식및 CD4+ 세포는 IFN- IL-2의생성, CD8+ 세포는 IFN- 의생성을증가시킨다고보고하였는데홍삼시료의항암치료에활용가능성을시사하였다. 18) 김등은정관장홍삼의물 extract, 식용발효주정 extract 및홍삼추출물로부터분리제조한 crude saponin을이용하여면역반응을매개하는수지상세포의활성효과에대하여알아보았다. 그결과홍삼시료중, crude saponin 을처리하였을때수지상세포의세포표면분자인 major histocompatibility complex (MHC) class II, CD40, CD80, CD86의발현이증가하였으며, phagocytosis는감소하였다. 또한홍삼시료를처리한수지상세포와 allogeneic T세포를함께배양하였을때, 홍삼시료의물 extract, 식용발효주정 extract, crude saponin 모두 allogeneic T 세포의증식반응을유도하였고, IL-2와의생산량을증가시키는것을확인하였다. 또한 syngeneic T세포와 syngeneic T세포의반응에서도 T세포의증식반응을높게유도하였으며, syngeneic T세포에서 IL-2와의생산량을증가 시키고, syngeneic T세포에서는생산량을증가시키는것을확인하였다. 이상의결과로 crude saponin의경우수지상세포의세포표면공동자극분자의발현을유도하고성숙을유도함으로써 T세포의활성을증진시키는것으로생각되며, 물 extract와식용발효주정 extract는 crude saponin과는다른기작으로 T세포활성화를유도한다는보고가있다. 19) 대식세포는체액성면역에서는 B림프구와 T림프구의활성에관여하며세포성면역에서는감염균이나종양세포에직접치사활성을나타낸다. 인삼은종양세포를직접사멸시키지않고대식세포를통하여세포사멸을하였다. 최등은종양세포로 L929와 EL4를사용하였고전등은 S180과 L929를사용하여인삼사포닌과 triol사포닌의대식세포치사활성의현저한증가를관찰하였는데후자는인삼사포닌이대식세포에 tumor necrosis factor (TNF) 분비를자극하는반면 Cyclophosphamide는관련이없음을밝혔다 ) 김등은열처리인삼으로부터얻은메탄올추출물과 ether 및 BuOH 가용분획의nitrogen monoxide (NO) 생성유도활성을평가하기위하여분획단독또는 IFN-와병용처리한후, 대식세포로부터생성된 NO의생성량을측정하고마찬가지로백삼으로부터동일한처리를하여, 열처리인삼에서 NO합성유도가고유한효과로나타남에따라인삼의항암효과를강화시킬수있다고하였다. 22) Kumar는인삼이생쥐의복강침출대식세포의 NO 생성을촉진하고대식세포의 -glucosinidase의 acid phosphatase의활성을촉진하며대식세포이동지수를 4배이상증가시켰는데대식세포는생체방어의제1선이기때문에대식세포의활성화는중요성이크다는것이다. 23) 박등은인삼을 water extract of Panax notoginseng (WEPN) 이 caspase-3을활성화하여 Lung carcinoma를 apoptosis한다고하였다. 24)

4 148 大田大學校韓醫學硏究所論文集第 19 卷第 2 號 암세포는 2mm이상으로커지면초기세포는허혈화되고신생혈관형성으로전이된부위에산소와영양분을공급받아서다른부위에다시암세포의새로운성장과촉진을하게되므로신생혈관을억제하는것은암치료에중요한부분이다. Cyclophosphamide와사포닌의병용투여가각각의단독투여보다항암효과가컸으며, 인삼의에탄올불용성분획물이 benzopyrene (BP) 에의한폐암발생을억제함을관찰하고이분획이면역조절자로서항암효과가있음을제시하였다. 중국산백삼과홍삼의종양을가진생쥐의면역강화효과, HIV 감염자에게 azidothymidine (AZT) 와홍삼의동시투여가면역기능을현저히증가시켜발병지연유도, 위암환자의수술후 1 년간홍삼분말투여로면역기작방식으로의항암효과가있음이보고되었다 ) RGAP가대식세포를활성화시킴으로써흑색종양세포의성장과폐전이를억제한다고하였고 30), 소화관에서대사된스테로이드정인삼사포닌의최종산물인 M1과 M4에의해촉진된수지상세포의성숙은강력한 Th1의극성화 (polarization) 를야기한다고보고하였다. M1과 M4는각각 protopanaxadiol (PPD) 와 protopanaxatriol (PPT) 에서기원하며 DC는적응면역반응의개시에서지렛대이며암에대한면역반응의유도에열쇠로인식되고있다. 인삼사포닌대사물의효과적작용은이약의항종양작용과관련될것이라고보고하였다 ) 인삼은바이러스에감염된쥐에서면역억제혹은면역조절효과가있으며암예방효과에는면역감시체계증강, 세포내방어기전증강, 항돌연변이, 혈관생성억제, 증식억제, 세포자멸사등의기전이관여하는것으로알려져있다 ) Ⅳ. 고찰및결론 인삼의항암작용은세포사멸촉진, 신생혈관억제촉진, 재발방지, 전이억제등을포함하여암세포성장주기를차단하며암발생의예방으로나눌수있다. 기존의여러연구에서각각의항암작용 의기전은인삼의다양한추출방식에따른개별적인성분들의단일하거나또는복합적인작용에의거한다고할수있다. 한의학에서인삼은예로부터많이이용하는한약재이며특히세계적으로도많이소모되는제품에도포함되어있다. 전통적인한의학에서인삼의효능은大補元氣, 建碑益氣, 止渴生津, 安神益智등으로요약할수있다. 간략하게살펴보면음식이인체에들어오면後天之氣에해당하는脾臟의運化作用을통해물질대사의한축인영양성분의생성이되므로이를後天之精이라고한다. 이러한물질생성이부족해지는상황에서무리한熱生産이가속되었을때인체는과도한근육사용으로인한허탈감과피로감에빠질수밖에없다. 결국이러한脾主運化의작용이약해짐으로인한체액의감소에따른인체의身熱, 自汗, 倦怠등의증세가나타날때인삼을투여하게된다. 인체는氣, 血, 津液이서로공존하면서각각독립적으로존재하지않고항상상대적으로균형과조절을통해서인체생명활동을유지하므로氣의문제는곧津液의생성과血에도영향을끼치게되는것이다. 인삼의여러작용이있지만특히이러한기의병리적인상황하에서나타나는환자들의증상을면밀히관찰하여인삼의氣味 Q과성분적인藥理學적인면을모두고려하는것이좀더인삼의전체적인효용을알수있으리라고사료되며, 특히기존의서양의학적암치료의공격적인요법에비해서좀더암환자의전체적인상황을고려한전인의학의관점에서볼때인삼의항암작용을이용한암치료와암예방은환자들에게크게기여리라고추측된다. 이상에서인삼의항암작용기전을살펴보고고찰한결과인삼의항암작용은단일한성분의효과로나타나기도하고복합적인작용을통해서나타날수도있다. 성분에따라항체와 cytokine, NK세포, 대식세포등이여러작용을통한암세포의치료에응용할수있다는연구결과들을확인하였다. 특히공격적인암세포의치료에또다른한의

5 인삼의항암작용에대한한의학관련논문분석 149 학적항암치료는암진행을억제하며세포사멸촉진, 신생혈관억제촉진, 재발방지, 전이억제, 암예방효과등다양한부분으로전략적인접근을하는것이특징이다. 예로부터널리사용되고있는인삼의항암작용에대한연구가많이진행되어인삼사포닌의대식세포활성화를통한암전이세포제거, RGAP 에의한대식세포의종양치사활성화와비장의 NK세포의활성증가에따라흑색종양세포의폐전이억제효과, 진세노사이드의최종대사산물이 M1.M4의항암작용등이발표되었다. 인삼의항암기전이각각의기전마다그유효성이차이가나는부분이있으므로환자의상태와병기에적합한인삼의정확한투여가항암효과를극대화시킬것으로생각되며인삼성분의항암기전에대한유전자및단백질발현에대해서전반적인실험을통한구체적인기전제시가앞으로좀더진행되어야할것으로사료된다. 참고문헌 1. 통계청. 2009년한국의사회지표 권창현, 유화승, 이연월, 조종관. 보완대체의학의암치료연구현황 - MEDLINE을중심으로 -. 한방종양학회지, 10(1);57-74, 윤성우, 박재우. 중국의암치료현황 - ' 중의중서의결합잡지 ' 를중심으로 -. 한방종양학회지, 11(1);65-73, Jun Wen, Elizabeth A. Zimmer. Phylogeny and Biogeography of PanaxL. (the Ginseng Genus, Araliaceae). Inferences from ITS Sequences of Nuclear Ribosomal DNA.Molecular Phylogenetics and Evolution, 6(2); , 박종대. 고려인삼의화학성분에관한고찰. 고려인삼학회지, 20(4); , 정노팔. 면역증강ㆍ조절효과. 고려인삼학회. 最新高麗人蔘硏究 (Ⅰ), 12: , 유화승. 통합종양학. 이퍼블릭 , 133, Kim KyungSuk, Pyo SuhKneung, Sohn EunHwa. Immunomodulation of NK Cell activity by Red Ginseng Acidic Polysaccharide (RGAP) in Ovariectomized Rats, J. Ginseng Res, 33(2):99-103, Yun YS, Moon HS, Oh YR, Jo SK, Kim YJ and Yun TK. Effect of red ginseng on natural killer cell activity in mice with lung adenoma induced by urethan and benzo(a)pyrene.cancer Detection and Prevention, : , 김미나, 정노팔. 생쥐의자연살해세포에미치는인삼분획물들의영향. 고려인삼학회지, 13(2): , Kim JY, Germolec DR and Luster MI. Panax ginseng as a potential immunomodulator:studies in mice. Immunopharmacology and Immunotoxicology, 12(2): , Yun YS., Lee YS., Jo SK and Jung IS. Inhibition of antochthonous tumor by ethanol insoluble fraction from Panax ginseng as an immunomodulator. Planta Medica, 59(6): , 김기환, 정인성, 정희용, 조성기, 윤연숙. 홍삼다당체의항암면역증강작용연구. 고려인삼학회지, 21(2):78-84, 서성옥, 정철현, 조민영, 손길수. 소화기계암의수술후면역기능에대한고려홍삼의효과. 고려인삼학회지, 22(1):32-42, Park JD, Kim YS, Shin HJ, Park KM, Kwak YS and Toida T.Antitumor activities of red ginseng acidic polysaccharide(rgap) as an immunomodulator. Planta Med, 70(11): , Kim YS, Park KM, Shin HJ, Song KS,

6 150 大田大學校韓醫學硏究所論文集第 19 卷第 2 號 Nam KY and Park JD. Anticancer activities of red ginseng acidic polysaccharide by activation of macrophage and natural killer cells.yachak Hoeji, 46: , Choi JH, Han EH and Jeong HG. Inhibitory effects of red ginseng saponin on lung metastasis of murine meloma through enhanced immune stimulation and suppression of matrix metalloproteinases. 고려인삼학회 2007년도춘계학술대회, 25, 김도순, 박정은, 서권일, 고성룡, 이종원, 도재호, 이성태. 고려홍삼의수지상세포활성효과. 고려인삼학회지, 30(3): , 김웅, 정노팔. 생쥐대식세포의 K562 종양세포치사활동에미치는인삼분획물의영향. 고려인삼학회지, 13(2):24-29, 최상운, 정노팔, 김세창. 생쥐대식세포의종양세포치사활성에미치는인삼분획물과지방다당류의영향. 고려인삼학회지, 14(3): , 전혜경, 김세창, 정노팔. 생쥐의대식세포종양치사활성과항암효과에미치는사포닌분획과 Cyclophosphamide의영향. 고려인삼학회지, 15(2):99-105, 김지연, 이화진, 김지선, 안한나, 류재하. 인삼사포닌에의한대식세포일산화질소생성유도. 약학회지, 49(1):80-85, Kumar Ashok. Immunomodulatory Response Induced by Ginseng.Proc. 8th Int.Symposium on Ginseng, , Park SeungChan, Yoo HwaSeung, Park Cheol,Cho ChongKwan, Kim GiYoung, Kim WunJae, Lee YeonWeol, Choi YungHyun. Induction of apoptosis in human lung carcinoma cells by the water extract of Panax notoginseng is associated with the activation of caspase-3 through downregulation of Akt. International journal of oncology, 35(1): , 전혜경, 김세창, 정노팔. 생쥐의대식세포종양치사활성과항암효과에미치는인삼 Saponin 분획물과 Cyclophosphamide 의영향. 고려인삼학회지, 15(2):99-105, Yun YS, Lee YS, Jo SK and Jung IS. Inhibition of antochthonous tumor by ethanol insoluble fraction from Panax ginseng as an immunomodulator.planta Medica, 59(6): , Yang LL., Yu WC and Yen KY. Immunopotentiator in Chinese medical ginseng..proc. 6th Int. Symposium on Ginseng, 49-51, Shin YO, Cho YK. Ki MK, Lee JS, Nam JG, Choi MK, Kim YB and Choi KW. Effect of Korean red ginseng on immunological markers of persons with human immunodeficiency virus.proc. 6th Int. Symposium on Ginseng, 52-56, Woo YM, Lee HW and Kim JP. The effect of ginseng on the postoperative nutritional status and immune functions of gastric carcinoma patients. Proc.6th Int.Symposium on Ginseng, 61-65, Shin HJ, Kim YS, Kwak YS, Song YB, Kyung JS, Wee JJ and Park JD. A further study on the inhibitation of tumor growth and metastasis by RGAP.Natural Products Science, 10: , Takei MT, achikawa E, Hasegawa H and Lee JJ. Dendritie cells maturation promped by M1 and M4, end prouct of steroidal ginseng saponins metabolized in

7 인삼의항암작용에대한한의학관련논문분석 151 digestive tracts,drive a potent Th1 polarization.biochem Pharmacol, 68(3): , Takei M, Tachikawa E, Takahashi T, Hasegawa H and Taira E. Metabolized ginseng saponins promote maturation of dendritic cells,which drive a potent polarization of naive T cells toward a helper T cell type 1. Proc. 9th Int. Symposium on Ginseng, , 신해림, 김준연, 이덕희, 윤택구, Gareth Morgan,Harri Vainio. 인삼항암효과에관한 문헌고찰-실험연구와역학연구결과를중 심으로 예방의학회지, 33(4): , Yeung HW, Cheung,Leung KL. Immunopharmcology of chinese medicine 1, Ginseng induced immunosuppression in virus-infected mice.am J Chinese Med, 10(1-4):44-54, Singh V, Agarwal S, Gupta B. Immunomodulatory activity of Panax ginseng extract Planta Med, 50(6): , Jie Y, Cammisuli S, Baggiolini M. Immunomodulatory effexts of Panax Ginseng C. A. Meyer in the mouse, Agents and Actiongs, 15(3-4): , Kenarova B, Neychev H, Hadjiivanova C, Petkov V. Immunomodulating activity of ginsenoside Rg1 from Panax Ginseng. Japan J Phamacol, 54(4): , Kim YJ, Gemolec DR, luster MI, Panax ginseng as a potential immunomodulator:studies in mice. Immunopharmacology and Immunotoxicology, 12(2): , 박민경, 황우익. 인삼 Petroleumether 추 출물이종양세포의증식주기진행및 Protein Kinas C의활성에미치는영향. 고려인삼학회지, 20(3): , Umnova N, Michurina T, Smironova N, Aleksandrova I, Poroshenko G. In vitro and in vivo studies of bioginseng antimutagen properties in mammalian cells. Biull Eksp Biol Med, 111(5): , Mochizuki M, Yoo Y, Matsuzawa K, Sato K, Saiki I, et al. Inhibitory effect of tumor matastasis in mice by saponins Ginsenoside- Rb2, 20(R)-and 20(S)- ginsenoside Rg3, of Red ginseng. Biol Pharm Bull., 18(9): , Liu WK, Xu SX, Che TX. Anti-proliferative effect of ginseng saponins on human prostate cancer cell line. Life Sci, 67(11): , Kim SE, Lee YH, Park JH, Lee SK. Gin-senoside-Rs4, a new type of ginseng saponin concurrently induces apoptosis and selec-tively elevates protein levels of p53 and p21waf1 in human hepatoma SK-HEP-1 celss. Eur J Cancer, 35(3): , 1999.

Jkbcs016(92-97).hwp

Jkbcs016(92-97).hwp Expression of bcl-2 and Apoptosis and Its Relationship to Clinicopathological Prognostic Factors in Breast Cancer - A Study with Long Term Follow-up correlated with the survival rate.(journal of Korean