华蟾素抗肿瘤研究进展
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摘要
华蟾素是我国传统中药材中华大蟾蜍干皮的提取物,其主要成分为蟾毒内酯类、生物碱类、多肽类、胆固醇类等。随着对华蟾素药理作用的深入研究,已证实华蟾素在抗炎、抗病毒、抗肿瘤、消肿止痛等方面具有重要的应用价值。近年来,华蟾素的抗肿瘤活性逐渐被国内外学者重视。分子药理学研究表明,华蟾素主要通过增强机体免疫功能、抑制肿瘤细胞增殖、诱导肿瘤细胞凋亡、逆转肿瘤细胞多药耐药性以及抑制肿瘤血管生成等多种途径发挥抗肿瘤作用。华蟾素诱导细胞凋亡的机制涉及广泛,包括死亡受体介导的外源性信号通路和线粒体参与的内源性信号通路,有多种酶或蛋白参与了华蟾素诱导细胞凋亡的过程。临床研究表明,华蟾素作为临床上常用的抗肿瘤中药制剂,具有低毒、副作用少、抗癌谱广等特点,广泛应用于肝癌、胃癌、肺癌、结肠癌、食管癌、胆囊癌、非霍奇金淋巴瘤等发病率较高的肿瘤的治疗,无论单独应用还是与其他药物联合应用均表现出良好疗效,单独应用时,对中晚期肿瘤患者具有较好疗效,联合应用时,可以提高疗效,减少不良反应。为了促进华蟾素抗肿瘤活性的研究,扩大其应用前景,本文通过对华蟾素近年来相关文献的整理归纳,对其抗肿瘤机制的研究进展及其在临床上的应用做一综述,以供实验研究及临床参考。
Cinobufacini is an extract from skin of Bufo gargarizans,and composed of bufadienolides,peptides,alkaloids and cholesterol. With the deepening of research of its pharmacological effect,it has been proved that cinobufacini has important application value in anti-inflammation,anti-virus,anti-tumor,as well as swelling and pain relief. In recent years,more attention has been given to its anti-tumor activity. The molecular pharmacology studies showed that cinobufacini plays an important role on anti-tumor by enhancing the immunity,inhibiting the proliferation of tumor cells,inducing the apoptosis of tumor cells,reversing multidrug resistance of tumor cells,and inhibiting the tumor angiogenesis. Both intrinsic pathway mediated by mitochondria and extrinsic pathway mediated by death receptor are involved in cinobufacini-induced apoptosis. Clinical studies have shown that cinobufacini is broadly used as an anti-tumor traditional Chinese medicine,due to its advantages of low toxicity,less side effects,and wide anticancer spectrum. It is broadly used in the treatment of liver cancer,gastric carcinoma, lung cancer, colon cancer, esophageal carcinoma, carcinoma of gallbladder, and nonHodgkinlymphoma. Either single or combined application plays an active role in improving the efficacy and reducing side effects. To promote the research of anti-tumor activity of cinobufacini,and expand its application prospects,this review focuses on anti-tumor mechanism and clinical application of cinobufacini.
Cinobufacini is an extract from skin of Bufo gargarizans,and composed of bufadienolides,peptides,alkaloids and cholesterol. With the deepening of research of its pharmacological effect,it has been proved that cinobufacini has important application value in anti-inflammation,anti-virus,anti-tumor,as well as swelling and pain relief. In recent years,more attention has been given to its anti-tumor activity. The molecular pharmacology studies showed that cinobufacini plays an important role on anti-tumor by enhancing the immunity,inhibiting the proliferation of tumor cells,inducing the apoptosis of tumor cells,reversing multidrug resistance of tumor cells,and inhibiting the tumor angiogenesis. Both intrinsic pathway mediated by mitochondria and extrinsic pathway mediated by death receptor are involved in cinobufacini-induced apoptosis. Clinical studies have shown that cinobufacini is broadly used as an anti-tumor traditional Chinese medicine,due to its advantages of low toxicity,less side effects,and wide anticancer spectrum. It is broadly used in the treatment of liver cancer,gastric carcinoma, lung cancer, colon cancer, esophageal carcinoma, carcinoma of gallbladder, and nonHodgkinlymphoma. Either single or combined application plays an active role in improving the efficacy and reducing side effects. To promote the research of anti-tumor activity of cinobufacini,and expand its application prospects,this review focuses on anti-tumor mechanism and clinical application of cinobufacini.
引文
[1]党欢,冯斌,王鹏远,等.九节龙皂苷抗肿瘤作用研究进展[J].中国实验方剂学杂志,2015,21(14):216-221.
[2]焦延娜,韩淑燕.抗癌中药单体对肿瘤细胞自噬的调控[J].中国实验方剂学杂志,2017,23(7):206-214.
[3]李晓花,李海涛,金玲钰,等.傣百解提取物对人肺癌A549裸鼠移植瘤的影响[J].中国实验方剂学杂志,2017,23(2):104-108.
[4]高学敏.中药学[M]. 2版.中国中医药出版社,2007:513-513.
[5]袁梅美,惠起源.华蟾素抗恶性肿瘤的研究进展[J].中国医药导报,2014,11(2):44-46.
[6]姜秋雯,陈涛.华蟾素抗恶性肿瘤的机制及不良反应的研究[J].时珍国医国药,2015,26(11):2737-2739.
[7]梁朝晖,张维彬,汪波.华蟾素在肿瘤防治中的意义[J].现代中西医结合杂志,2002,11(15):1512-1513.
[8]贾小晴,孙萍.华蟾素抗肿瘤成分及作用机制研究进展[J].辽宁中医药大学学报,2017,19(3):215-217.
[9] SU Y H,HUANG X Q,ZHANG D Z,et al. HPLC separation and determination of bufadienolide in Cinobufacini injection[J]. Chinese Trad Patent Med,2003,25(1):24-27.
[10]吴旭,高波,杨健,等.华蟾素注射液多肽成分体外抗肿瘤活性研究[J].药学学报,2012,47(6):822-826.
[11]韩鸿彬,陈嘉勇.华蟾素抗肿瘤作用及其机制的研究进展[J].中国肿瘤生物治疗杂志,2005,12(2):160-162.
[12]刘莉,蒋亚生,张士华,等.抗癌中药制剂局部注射对裸鼠人肝癌细胞核DNA含量的影响[J].中国肿瘤临床,1993,20(2):140-142.
[13]张振玉,张昆和,王崇文,等.华蟾素对三种消化系肿瘤细胞杀伤机制研究[J].中药药理与临床,1999,15(5):28-29.
[14]高畅,杨美春,莫新欣,等.中药及其活性成分在抗肿瘤中对细胞周期影响的研究进展[J].中国医疗前沿,2012,7(5):12-13.
[15]李泉旺,孙韬,胡凯文.华蟾素抗肿瘤机制的研究进展[J].中华中医药杂志,2010,25(12):2075-2078.
[16] WU Q,LIN W D,LIAO G Q,et al. Antiproliferative effects of cinobufacini on human hepatocellular carcinoma Hep G2 cells detected by atomic force microscopy[J]. World J Gastroenterol,2015,21(3):854-861.
[17] MA L,SONG B,JIN H,et al. Cinobufacini induced MDA-MB-231 cell apoptosis-associated cell cycle arrest and cytoskeleton function[J]. Bioorg Med Chem Lett,2012,22(3):1459-1463.
[18]李鹏,李祺福,黄胤怡.肿瘤治疗的新途径——中药有效成分诱导恶性肿瘤细胞分化[J].生物学通报,2002,37(3):8-11.
[19] Ghavami S,Hashemi M,Ande S R,et al. Apoptosis and cancer:mutations within caspase genes[J]. J Med Genet,2009,46(8):497-510.
[20]史新惠,王芳.肺癌中相关凋亡分子的新近研究进展[J].医学综述,2014,20(10):1729-1732.
[21] Hellebrand E E, Varbiro G. Development of mitochondrial permeability transition inhibitory agents:a novel drug target[J]. Drug Discov Ther,2010,4(2):54-61.
[22] QI F,LI A,Inagaki Y,et al. Antitumor activity of extracts and compounds from the skin of the toad bufo gargarizans cantor[J]. Int Immunopharmacol,2011,11(3):342-349.
[23] QI F,LI A,Inagaki Y,et al. Induction of apoptosis by cinobufacini preparation through mitochondria-and Fasmediated caspase-dependent pathways in human hepatocellular carcinoma cells[J]. Food Chem Toxicol,2012,50(2):295-302.
[24]邵淑丽,刘盛楠,张蕾,等.华蟾素诱导人胃癌SGC-7901细胞凋亡[J].基因组学与应用生物学,2015,34(9):1826-1832.
[25] Efuet E T,DING X P,Cartwright C,et al. Huachansu mediates cell death in non-Hodgkin's lymphoma by induction of caspase-3 and inhibition of MAP kinase[J]. Int J Oncol,2015,47(2):592-600.
[26]盛秀胜,徐玲娟.华蟾素诱导人红白血病细胞K562凋亡及对Caspase-3表达的影响[J].实用肿瘤杂志,2007,22(1):32-36.
[27]高山,田莉莉,陈华,等.华蟾素注射液对人肝癌Hep G-2细胞增殖及拓扑异构酶表达的影响[J].中国实验方剂学杂志,2013,19(11):250-255.
[28]张莉,李军民,钱樱,等.华蟾素诱导U937细胞凋亡及其作用机制[J].肿瘤,2007,27(5):341-344.
[29]赵昕,姜义,赵颖,等.华蟾素通过激活caspase3诱导He La细胞凋亡[J].中国实验诊断学,2018,22(2):330-333.
[30] XIA J,Inagaki Y,GAO J,et al. Combination of cinobufacini and doxorubicin increases apoptosis of hepatocellular carcinoma cells through the Fas-and mitochondria-mediated pathways[J]. Am J Chin Med,2017,45(7):1537-1556.
[31] HUANG T,GONG W H,LI X C,et al. Efficient killing effect of osteosarcoma cells by cinobufacini and cisplatin in combination[J]. Asian Pac J Cancer Prev,2012,13(6):2847-2851.
[32] WANG D,BI Z. Bufalin inhibited the growth of human osteosarcoma MG-63 cells via down-regulation of Bcl-2/Bax and triggering of the mitochondrial pathway[J].Tumour Biol,2014,35(5):4885-4890.
[33] ZHAI X,FANG F,LIU Q,et al. MiR-181a contributes to bufalin-induced apoptosis in PC-3 prostate cancer cells[J]. BMC Complement Altern Med,2013,13(1):1-6.
[34] MENG Q,YAN Z,AN L X,et al. Inhibitory effect of bufalin on retinoblastoma cells(HXO-RB44)via the independent mitochondrial and death receptor pathway[J]. Am J Transl Res,2016,8(11):4968-4974.
[35] YIN J Q,WEN L,WU L C,et al. The glycogen synthase kinase-3β/nuclear factor-kappa B pathway is involved in cinobufagin-induced apoptosis in cultured osteosarcoma cells[J]. Toxicol Lett,2013,218(2):129-136.
[36]袁斐,白钢钢,苗筠杰,等.中药逆转肿瘤细胞多药耐药的研究进展[J].中草药,2014,45(6):857-863.
[37] Borst P,Evers R,Kool M,et al. A family of drug transporters:the multidrug resistance-associated proteins[J]. J Natl Cancer Inst J,2000,92(16):1295-1302.
[38] Takara K,Sakaeda T,Okumura K. An update on overcoming MDR1-mediated multidrug resistance in cancer chemotherapy[J]. Curr Pharm Des,2006,12(3):273-286.
[39]张诚,万鼎铭,曹伟杰.华蟾素对Raji/ADR细胞多药耐药的逆转作用及机制[J].中国实验血液学杂志,2014,22(5):1306-1310.
[40]马继恒,华海清.中药抗肿瘤血管生成研究进展[J].肿瘤研究与临床,2010,22(2):141-144.
[41]刘浩,林洪生,花宝金,等.华蟾素调控VEGF/VEGFR-2信号传导抑制肿瘤血管生成的研究[J].中华中医药学刊,2008,26(11):2489-2491.
[42]刘祥胜,刘开俊,杨业金.华蟾素对Hela细胞生长和小鼠脾淋巴细胞分泌IL-2的影响[J].免疫学杂志,2005,21(b06):132-135.
[43]薛瑞,张青松,张玉洁,等.华蟾素对乳腺癌MCF-7移植瘤裸鼠的抗肿瘤作用及机制研究[J].实用药物与临床,2014,17(7):815-817.
[44] WANG J Y,CHEN L,ZHENG Z,et al. Cinobufocini inhibits NF-κB and COX-2 activation induced by TNF-αin lung adenocarcinoma cells[J]. Oncol Rep,2012,27(5):1619-1624.
[45]王志超,冯正平,王宏.华蟾素治疗中晚期肝癌的近期疗效观察[J].现代医院,2008,8(6):56-57.
[46] SUN T,ZHANG Y,SHEN Y,et al. A case of advanced lung cancer with malignant pericardial effusion treated by intrapericardial Cinobufacini injection instillation[J]. BST,2014,8(4):235-239.
[47]刘金鹏,江静,魏辉,等.华蟾素联合XELOX方案治疗晚期结肠癌的临床疗效观察[J].西部医学,2017,29(11):1560-1563.
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[50]刘怀民,郑玉玲,刘晓莉,等.华蟾素联合化疗治疗中晚期食管癌[J].中国实验方剂学杂志,2011,17(5):235-237.
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[2]焦延娜,韩淑燕.抗癌中药单体对肿瘤细胞自噬的调控[J].中国实验方剂学杂志,2017,23(7):206-214.
[3]李晓花,李海涛,金玲钰,等.傣百解提取物对人肺癌A549裸鼠移植瘤的影响[J].中国实验方剂学杂志,2017,23(2):104-108.
[4]高学敏.中药学[M]. 2版.中国中医药出版社,2007:513-513.
[5]袁梅美,惠起源.华蟾素抗恶性肿瘤的研究进展[J].中国医药导报,2014,11(2):44-46.
[6]姜秋雯,陈涛.华蟾素抗恶性肿瘤的机制及不良反应的研究[J].时珍国医国药,2015,26(11):2737-2739.
[7]梁朝晖,张维彬,汪波.华蟾素在肿瘤防治中的意义[J].现代中西医结合杂志,2002,11(15):1512-1513.
[8]贾小晴,孙萍.华蟾素抗肿瘤成分及作用机制研究进展[J].辽宁中医药大学学报,2017,19(3):215-217.
[9] SU Y H,HUANG X Q,ZHANG D Z,et al. HPLC separation and determination of bufadienolide in Cinobufacini injection[J]. Chinese Trad Patent Med,2003,25(1):24-27.
[10]吴旭,高波,杨健,等.华蟾素注射液多肽成分体外抗肿瘤活性研究[J].药学学报,2012,47(6):822-826.
[11]韩鸿彬,陈嘉勇.华蟾素抗肿瘤作用及其机制的研究进展[J].中国肿瘤生物治疗杂志,2005,12(2):160-162.
[12]刘莉,蒋亚生,张士华,等.抗癌中药制剂局部注射对裸鼠人肝癌细胞核DNA含量的影响[J].中国肿瘤临床,1993,20(2):140-142.
[13]张振玉,张昆和,王崇文,等.华蟾素对三种消化系肿瘤细胞杀伤机制研究[J].中药药理与临床,1999,15(5):28-29.
[14]高畅,杨美春,莫新欣,等.中药及其活性成分在抗肿瘤中对细胞周期影响的研究进展[J].中国医疗前沿,2012,7(5):12-13.
[15]李泉旺,孙韬,胡凯文.华蟾素抗肿瘤机制的研究进展[J].中华中医药杂志,2010,25(12):2075-2078.
[16] WU Q,LIN W D,LIAO G Q,et al. Antiproliferative effects of cinobufacini on human hepatocellular carcinoma Hep G2 cells detected by atomic force microscopy[J]. World J Gastroenterol,2015,21(3):854-861.
[17] MA L,SONG B,JIN H,et al. Cinobufacini induced MDA-MB-231 cell apoptosis-associated cell cycle arrest and cytoskeleton function[J]. Bioorg Med Chem Lett,2012,22(3):1459-1463.
[18]李鹏,李祺福,黄胤怡.肿瘤治疗的新途径——中药有效成分诱导恶性肿瘤细胞分化[J].生物学通报,2002,37(3):8-11.
[19] Ghavami S,Hashemi M,Ande S R,et al. Apoptosis and cancer:mutations within caspase genes[J]. J Med Genet,2009,46(8):497-510.
[20]史新惠,王芳.肺癌中相关凋亡分子的新近研究进展[J].医学综述,2014,20(10):1729-1732.
[21] Hellebrand E E, Varbiro G. Development of mitochondrial permeability transition inhibitory agents:a novel drug target[J]. Drug Discov Ther,2010,4(2):54-61.
[22] QI F,LI A,Inagaki Y,et al. Antitumor activity of extracts and compounds from the skin of the toad bufo gargarizans cantor[J]. Int Immunopharmacol,2011,11(3):342-349.
[23] QI F,LI A,Inagaki Y,et al. Induction of apoptosis by cinobufacini preparation through mitochondria-and Fasmediated caspase-dependent pathways in human hepatocellular carcinoma cells[J]. Food Chem Toxicol,2012,50(2):295-302.
[24]邵淑丽,刘盛楠,张蕾,等.华蟾素诱导人胃癌SGC-7901细胞凋亡[J].基因组学与应用生物学,2015,34(9):1826-1832.
[25] Efuet E T,DING X P,Cartwright C,et al. Huachansu mediates cell death in non-Hodgkin's lymphoma by induction of caspase-3 and inhibition of MAP kinase[J]. Int J Oncol,2015,47(2):592-600.
[26]盛秀胜,徐玲娟.华蟾素诱导人红白血病细胞K562凋亡及对Caspase-3表达的影响[J].实用肿瘤杂志,2007,22(1):32-36.
[27]高山,田莉莉,陈华,等.华蟾素注射液对人肝癌Hep G-2细胞增殖及拓扑异构酶表达的影响[J].中国实验方剂学杂志,2013,19(11):250-255.
[28]张莉,李军民,钱樱,等.华蟾素诱导U937细胞凋亡及其作用机制[J].肿瘤,2007,27(5):341-344.
[29]赵昕,姜义,赵颖,等.华蟾素通过激活caspase3诱导He La细胞凋亡[J].中国实验诊断学,2018,22(2):330-333.
[30] XIA J,Inagaki Y,GAO J,et al. Combination of cinobufacini and doxorubicin increases apoptosis of hepatocellular carcinoma cells through the Fas-and mitochondria-mediated pathways[J]. Am J Chin Med,2017,45(7):1537-1556.
[31] HUANG T,GONG W H,LI X C,et al. Efficient killing effect of osteosarcoma cells by cinobufacini and cisplatin in combination[J]. Asian Pac J Cancer Prev,2012,13(6):2847-2851.
[32] WANG D,BI Z. Bufalin inhibited the growth of human osteosarcoma MG-63 cells via down-regulation of Bcl-2/Bax and triggering of the mitochondrial pathway[J].Tumour Biol,2014,35(5):4885-4890.
[33] ZHAI X,FANG F,LIU Q,et al. MiR-181a contributes to bufalin-induced apoptosis in PC-3 prostate cancer cells[J]. BMC Complement Altern Med,2013,13(1):1-6.
[34] MENG Q,YAN Z,AN L X,et al. Inhibitory effect of bufalin on retinoblastoma cells(HXO-RB44)via the independent mitochondrial and death receptor pathway[J]. Am J Transl Res,2016,8(11):4968-4974.
[35] YIN J Q,WEN L,WU L C,et al. The glycogen synthase kinase-3β/nuclear factor-kappa B pathway is involved in cinobufagin-induced apoptosis in cultured osteosarcoma cells[J]. Toxicol Lett,2013,218(2):129-136.
[36]袁斐,白钢钢,苗筠杰,等.中药逆转肿瘤细胞多药耐药的研究进展[J].中草药,2014,45(6):857-863.
[37] Borst P,Evers R,Kool M,et al. A family of drug transporters:the multidrug resistance-associated proteins[J]. J Natl Cancer Inst J,2000,92(16):1295-1302.
[38] Takara K,Sakaeda T,Okumura K. An update on overcoming MDR1-mediated multidrug resistance in cancer chemotherapy[J]. Curr Pharm Des,2006,12(3):273-286.
[39]张诚,万鼎铭,曹伟杰.华蟾素对Raji/ADR细胞多药耐药的逆转作用及机制[J].中国实验血液学杂志,2014,22(5):1306-1310.
[40]马继恒,华海清.中药抗肿瘤血管生成研究进展[J].肿瘤研究与临床,2010,22(2):141-144.
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