去甲斑蝥素和它的抗癌作用与机制

摘要/Abstract

摘要： 去甲斑蝥素是传统抗癌中药斑蝥的活性成分斑蝥素的去甲基衍生物, 近年在中国已作为一种常规的抗癌药物在临床应用。显然, 了解去甲斑蝥素的抗癌作用及其分子机制有益于其临床应用和推广。但有关这方面的讨论文章却很少。本文将重点介绍去甲斑蝥素的抗癌作用, 如诱导凋亡、抑制增殖、阻止侵袭转移、抗血管生成和/或抗血管生成拟态以及它们的分子机制。

关键词: 去甲斑蝥素, 抗癌药物, 凋亡, 侵袭, 血管生成, 血管生成拟态

Abstract: Norcantharidin (NCTD) is a demethylated derivative of cantharidin which is an anticancer active ingredient of traditional Chinese medicine,and currently used clinically as a routine anti-cancer drug in China.Distinctly,understanding the anticancer effects and molecular mechanisms of NCTD is an important key for NCTD that serves as an anticancer drug in clinic.But,NCTD’s anticancer effects and mechanisms remain to be rarely elucidated.Here,we will review the key anticancer effects of NCTD,such as inducing cell apoptosis,inhibiting cell proliferation,blocking tumor invasion and metastasis,anti-angiogenesis and/or anti-vasculogenic mimicry,and their molecular mechanisms.

Key words: Norcantharidin (NCTD), Anticancer agent, Apoptosis, Invasion, Angiogenesis, Vasculogenic mimicry

中图分类号:

R 285.5

范跃祖, 经巍, 孙建军. 去甲斑蝥素和它的抗癌作用与机制[J]. 外科研究与新技术, 2012, 1(1): 13-18.

Fan Yue-Zu, Jing Wei, Sun Jian-Jun. Norcantharidin and its anti-cancer effects and mechanisms[J]. 外科研究与新技术, 2012, 1(1): 13-18.

参考文献

[1] Wang GS.Medical uses of Mylabris in ancient China and recent studies[J].J Ethnopharmacol,1989,26(2):147-162.
[2] Ho YP,To KK,Au-Yeung SC,et al.Potential new antitumor agents from an innovative combination of demethylcantharidin,a modified traditional Chinese medicine,with a platinum moiety[J].J Med Chem,2001,44(13):2065-2068.
[3] Massicot F,Dutertre-Catella H,Pham-Huy C,et al.In vitro assessment of renal toxicity and inflammatory events of two protein phosphatase inhibitors cantharidin and nor-cantharidin[J].Basic Clin Pharmacol Toxicol,2005,96(1):26-32.
[4] Wu LT,Chung JG,Chen JC,et al.Effect of norcantharidin on N-acetyltransferase activity in HepG2 cells[J].Am J Chin Med,2001,29(1):161-172.
[5] Chang C,Zhu YQ,Mei JJ,et al.Involvement of mitochondrial pathway in NCTD-induced cytotoxicity in human hepG2 cells[J].J Exp Clin Cancer Res,2010,29:145.
[6] Li GQ,Zhang SJ,Lü JF,et al.Molecular mechanism of norcantharidin inducing apoptosis in liver cancer cells[J].Zhonghua Yi Xue Za Zhi,2010,90(30):2145-2148.
[7] Li XQ,Shao SH,Han XH,et al.Norcantharidin induces apoptosis in SMMC-7721 cells via the c-Jun-NH2-terminal kinase signaling pathways[J].Zhonghua Gan Zang Bing Za Zhi,2010,18(2):146-147.
[8] Li XQ,Shao SH,Fu GL,et al.Study on norcantharidin-induced apoptosis in SMMC-7721 cells through mitochondrial pathways[J].Chin J Integr Med,2010,16(5):448-452.
[9] Sun ZX,Ma QW,Zhao TD,et al.Apoptosis induced by norcantharidin in human tumor cells[J].World J Gastroenterol,2000,6(2):263-265.
[10] Fan YZ,Fu JY,Zhao ZM,et al.Effect of norcantharidin on proliferation and invasion of human gallbladder carcinoma GBC-SD cells[J].World J Gastroenterol,2005,11(16):2431-2437.
[11] Fan YZ,Fu JY,Zhao ZM,et al.The in vitro effect of norcantharidin on proliferation and invasion of human gallbladder carcinoma GBC-SD cells and its mechanism[J].Zhonghua Zhong Liu Za Zhi,2004,26(5):271-274.
[12] Fan YZ,Fu JY,Zhao ZM,et al.Inhibitory effect of norcantharidin on the growth of human gallbladder carcinoma GBC-SD cells in vitro[J].Hepatobiliary Pancreat Dis Int,2007,6(1):72-80.
[13] Fan YZ,Fu JY,Zhao ZM,et al.Influence of norcantharidin on proliferation,proliferation- related gene proteins proliferating cell nuclear antigen and Ki-67 of human gallbladder carcinoma GBC-SD cells[J].Hepatobiliary Pancreat Dis Int,2004,3(4):603-607.
[14] Fan YZ,Zhao ZM,Fu JY,et al.Anti-tumor mechanism of norcantharidin for the implanted tumors of human gallbladder carcinoma in nude mice in vivo[J].Zhonghua Wai Ke Za Zhi,2006,44(9):618-622.
[15] Fan YZ,Zhao ZM,Fu JY,et al.Norcantharidin inhibits growth of human gallbladder carcinoma xenografted tumors in nude mice by inducing apoptosis and blocking the cell cycle in vivo[J].Hepatobiliary Pancreat Dis Int,2010,9(4):414-422.
[16] Chen YJ,Kuo CD,Tsai YM,et al.Norcantharidin induces anoikis through Jun-N-terminal kinase activation in CT26 colorectal cancer cells[J].Anticancer Drugs,2008,19(1):55-64.
[17] Yang PY,Chen MF,Tsai CH,et al.Involvement of caspase and MAPK activities in norcantharidin-induced colorectal cancer cell apoptosis[J].Toxicol In Vitro,2010,24(3):766-775.
[18] Peng F,Wei YQ,Tian L,et al.Induction of apoptosis by norcantharidin in human colorectal carcinoma cell lines:involvement of the CD95 receptor/ligand[J].J Cancer Res Clin Oncol,2002,128(4):223-230.
[19] Peng C,Liu X,Liu E,et al.Norcantharidin induces HT-29 colon cancer cell apoptosis through the alphavbeta 6-extracellular signal-related kinase signaling pathway[J].Cancer Sci,2009,100(12):2302-2308.
[20] Huang Y,Liu Q,Liu K,et al.Suppression of growth of highly-metastatic human breast cancer cells by norcantharidin and its mechanisms of action.Cytotechnology,2009,59(3):201-208.
[21] Yang PY,Chen MF,Kao YH,et al.Norcantharidin induces apoptosis of breast cancer cells:involvement of activities of mitogen activated protein kinases and signal transducers and activators of transcription.Toxicol In Vitro,2011,25(3):699-707.
[22] Yi SN,Wass J,Vincent P,et al.Inhibitory effect of norcantharidin on K562 human myeloid leukemia cells in vitro[J].Leuk Res,1991,15(10):883-886.
[23] Li JL,Cai YC,Liu XH,et al.Norcantharidin inhibits DNA replication and induces apoptosis with the cleavage of initiation protein Cdc6 in HL-60 cells[J].Anticancer Drugs,2006,17(3):307-314.
[24] An WW,Wang MW,Tashiro SI,et al.Mitogen-activated protein kinase-dependent apoptosis in norcantharidin-treated A357-S2 cells is proceeded by the activation of protein kinase C[J].Chin Med J,2005,118(3):198-203.
[25] Kok SH,Hong CY,Kuo MY,et al.Comparisons of norcantharidin cytotoxic effects on oral cancer cells and normal buccal keratinocytes[J].Oral Oncol,2003,39(1):19-26.
[26] Yang EB,Tang WY,Zhang K,et al.Norcantharidin inhibits growth of human HepG2 cell-transplanted tumor in nude mice and prolongs host survival[J].Cancer Lett,1997,117(1):93-98。
[27] Chen YN,Chen JC,Yin SC,et al.Effector mechanisms of norcantharidin-induced mitotic arrest and apoptosis in human hepatoma cells[J].Int J Cancer,2002,100(2):158-165.
[28] Hong CY,Huang SC,Lin SK,et al.Norcantharidin-induced post-G (2)/M apoptosis is dependent on wild-type p53 gene[J].Biochem Biophys Res Commun,2000,276(1):278-285.
[29] Qiu Z,Zhu J,Harms JS,et al.Bovine herpesvirus VP22 induces apoptosis in neuroblastoma cells by upregulating the expression ratio of Bax to Bcl-2[J].Hum Gene Ther,2005,16(1):101-108.
[30] Zheng XL,Sun HX,Liu XL,et al.Astilbic acid induced COLO 205 cell apoptosis by regulating Bcl-2 and Bax expression and activating caspase-3[J].Acta Pharmacol Sin,2004,25(8):1090-1095.
[31] Bowen JM,Gibson RJ,Keefe DM,et al.Cytotoxic chemotherapy upregulates pro-apoptotic Bax and Bak in the small intestine of rats and humans[J].Pathology,2005,37(1):56-62.
[32] Kok SH,Cheng SJ,Hong CY,et al.Northaridin-induced apoptosis in oral cancer cells is associated with an increase of proapoptotic to antiapoptotic protein ratio[J].Cancer Lett,2005,217(1):43-52.
[33] Tomazic A,Pegan V,Ferlan-Marolt K,et al.Cyclin D1 and bax influence the prognosis after pancreatoduodenectomy for periampullary adenocarcinoma[J].Hepatogastroenterology,2004,51(60):1832-1837.
[34] Santini D,Tonini G,Vecchio FM,et al.Prognostic value of Bax,Bcl-2,p53,and TUNEL staining in patients with radically resected ampullary carcinoma[J].J Clin Pathol,2005,58(2):159-165.
[35] Morinaga S,Nakamura Y,Ishiwa N,et al.Expression of survivin mRNA associates with apoptosis,proliferation and histologically aggressive features in hepatocellular carcinoma[J].Oncol Rep,2004,12(6):1189-1194.
[36] Dai DJ,Lu CD,Lai RY,et al.Survivin antisense compound inhibits proliferation and promotes apoptosis in liver cancer cells[J].World J Gastroenterol,2005,11(2):193-919.
[37] An WW,Gong XF,Wang MW,Tashiro S,Onodera S,Ikejima T.Northaridin induces apoptosis in HeLa cells through caspase,MAKPK,and Mitochondrial pathways[J].Acta Pharmacol Sin,2004,25(11):1502-1508.
[38] Li GQ,Zhang SJ,Lü JF,et al.Molecular mechanism of norcantharidin inducing apoptosis in liver cancer cells[J].Zhonghua Yi Xue Za Zhi,2010,90(30):2145-2148.
[39] Liu XH,Blazsek I,Comisso M,et al.Effects of norcantharidin,a protein phosphatase type-2A inhibitor,on the growth of normal and malignant haemopoietic cells[J].Eur J Cancer,1995,31A(6):953-963.
[40] McCluskey A,Ackland SP,Gardiner E,et al.The inhibition of protein phosphatases 1 and 2A:a new target for rational anti-cancer drug design?[J].Anticancer Drug Des,2001,16(6):291-303.
[41] Baba Y,Hirukawa N,Tanohira N,et al.Structure-based design of a highly selective catalytic site-directed inhibitor of Ser/Thr protein phosphatase 2B (calcineurin)[J].J Am Chem Soc,2003,125(32):9740-9749.
[42] Hart ME,Chamberlin AR,Walkom C,et al.Modified norcantharidins; synthesis,protein phosphatases 1 and 2A inhibition,and anticancer activity[J].Bioorg Med Chem Lett,2004,14(8):1969-1973.
[43] Kirsch DG,Doseff A,Chau BN,et al.Caspase-3-dependent cleavage of Bcl-2 promotes release of cytochrome c[J].J Biol Chem,1999,274(30):21155-21161.
[44] Enari M,Sakahira H,Yokoyama H,et al.A caspase-activated DNase that degrades DNA during apoptosis and its inhibitor ICAD[J].Nature,1998,391(6662):43-50.
[45] Cheng EH,Kirsch DG,Clem RJ,et al.Conversion of Bcl-2 to a Bax-like death effector by caspases[J].Science,1997,278(5345):1966-1968.
[46] An WW,Wang MW,Tashiro S,et al.Norcantharidin induces human melanoma A375-S2 cell apoptosis through mitochondrial and caspase pathways[J].J Korean Med Sci,2004,19(4):560-566.
[47] Ramrez CJ,Haberbusch JM,Soprano DR,et al.Retinoic acid induced repression of AP-1 activity is mediated by protein phosphatase 2A in ovarian carcinoma cells[J].J Cell Biochem,2005,96(1):170-182.
[48] Davis RJ.MAPKs:new JNK expands the group[J].Trends Biochem Sci,1994,19(11):470-473.
[49] Garrington TP,Johnson GL.Organization and regulation of mitogenactivated protein kinase signaling pathways[J].Curr Opin Cell Biol,1999,11(2):211-218.
[50] Nelson JM,Fry DW.Akt,MAPK (Erk1/2),and p38 act in concert to promote apoptosis in response to ErbB receptor family inhibition[J].J Biol Chem,2001,276(18):14842-14847.
[51] Wu GS.The functional interactions between the p53 and MAPK signaling pathways[J].Cancer Biol Ther,2004,3(2):156-161.
[52] She QB,Huang C,Zhang Y,et al.Involvement of c-jun NH (2)-terminal kinases in resveratrol-induced activation of p53 and apoptosis[J].Mol Carcinog,2002,33(4):244-250.
[53] Chen YN,Cheng CC,Chen JC,et al.Norcantharidin-induced apoptosis is via the extracellular signal-regulated kinase and c-Jun-NH2-terminal kinase signaling pathways in human hepatoma HepG2 cells[J].Br J Pharmacol,2003,140(3):461-470.
[54] Chang C,Zhu YQ,Mei JJ,et al.Involvement of mitochondrial pathway in NCTD-induced cytotoxicity in human hepG2 cells[J].J Exp Clin Cancer Res,2010,29:145.
[55] Li XQ,Shao SH,Fu GL,et al.Study on norcantharidin-induced apoptosis in SMMC-7721 cells through mitochondrial pathways.Chin J Integr Med,2010,16(5):448-452.
[56] Liao HF,Chen YJ,Chou CH,et al.Norcantharidin induces cell cycle arrest and inhibits progression of human leukemic Jurkat T cells through mitogen-activated protein kinase-mediated regulation of interleukin-2 production.Toxicol In Vitro,2011,25(1):206-212.[57] Chen YJ,Shieh CJ,Tsai TH,et al.Inhibitory effect of norcantharidin,a derivative compound from blister beetles,on tumor invasion and metastasis in CT26 colorectal adenocarcinoma cells[J].Anticancer Drugs 2005,16(3):293-299.
[58] Chen YJ,Chang WM,Liu YW,et al.A small-molecule metastasis inhibitor,norcantharidin,downregulates matrix metalloproteinase-9 expression by inhibiting Sp1 transcriptional activity in colorectal cancer cells[J].Chem Biol Interact,2009,181(3):440-446.
[59] Huang G,Chen L.Tumor vasculature and microenvironment normalization:a possible mechanism of antiangiogenesis therapy[J].Cancer Biother Radiopharm,2008,23(5):661-667.
[60] Rhee J,Hoff PM.Angiogenesis inhibitors in the treatment of cancer[J].Expert Opin Pharmacother,2005,6(10):1701-1711.
[61] Sato M,Arap W,Pasqualini R.Molecular targets on blood vessels for cancer therapies in clinical trials[J].Oncology (Williston Park),2007,21(11):1346-1352.
[62] Maniotis AJ,Folberg R,Hess A,et al.Vascular channel formation by human melanoma cells in vivo and in vitro:vasculogenic mimicry[J].Am J Pathol,1999,155(3):739-752.
[63] Hendrix MJ,Seftor EA,Hess AR,et al.Molecular plasticity of human melanoma cells[J].Oncogene,2003,22(20):3070-3075.
[64] Vartanian AA,Stepanova EV,Gutorov SL,et al.Prognostic significance of periodic acid-Schiff-positive patterns in clear cell renal cell carcinoma[J].Can J Urol,2009,16(4):4726-4732.
[65] Sun BC,Zhang SW,Zhao XL,et al.Vasculogenic mimicry is associated with shorter survival in hepatocellular carcinomas[J].Lab Invest,2006,86:1302.
[66] Fan YZ,Sun W,Zhang WZ,et al.Vasculogenic mimicry in human primary gallbladder carcinomas and clinical significance thereof[J].Zhonghua Yi Xue Za Zhi,2007,87(3):145-149.
[67] Sun W,Fan YZ,Zhang WZ,et al.A pilot histomorphology and hemodynamic of vasculogenic mimicry in gallbladder carcinomas in vivo and in vitro[J].J Exp Clin Cancer Res,2011,30:46
[68] Sun W,Shen ZY,Zhang H,Fan YZ,Zhang WZ,Zhang JT,Lu XS,Ye C.Overexpression of HIF-1α in primary gallbladder carcinoma and its relation to vasculogenic mimicry and unfavourable prognosis[J].Oncol Rep,2012,27(6):1990-2002.
[69] Fan YZ.A new medical therapy model for the patients with cancer[J].J Tongji Univ (Med Sci),2009,30(1):1-6.
[70] Fan YZ,Sun W.Molecular regulation of vasculogenic mimicry in tumors and potential tumor-target therapy[J].World J Gastrointestinal Surg,2010,2(4):117-127.
[71] Fan YZ,Chen CQ,Zhao ZM,et al.Effects of norcantharidin on angiogenesis of human gallbladder carcinoma and its anti-angiogenic mechanisms[J].Zhonghua Yi Xue Za Zhi,2006,86(10):693-699.
[72] Zhang JT,Fan YZ,Chen CQ,et al.Norcantharidin:A potential antiangiogenic agent for gallbladder cancers in vitro and in vivo [J].Int J Oncol,2012,4(5):1501-1514.
[73] Chen YJ,Tsai YM,Kuo CD,et al.Norcantharidin is a small-molecule synthetic compound with anti-angiogenesis effect[J].Life Sci,2009,85(17-18):642-651.