通光散C_(21)甾体成分增强紫杉醇抗肿瘤作用的研究
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摘要
目的揭示中药通光散(Marsdenia Tenacissima)增强紫杉醇抗肿瘤作用的有效成分。方法 MTT法测定紫杉醇单独,或在无细胞毒浓度的通光散单体成分存在下对肿瘤细胞增殖的半数抑制浓度(IC50);在荷瘤裸鼠模型上测试紫杉醇单独、或与通光散单体成分联用时对肿瘤的抑制效果。结果通光散的5个C21甾体去氧糖苷[通光散新苷C(Tenacissimoside C,M-12)、Marsdenoside A(M-13)、Marsdenoside C(M-17),通光散新苷A(Tenacissimoside A,M-18)和Tenacissoside E(M-21)]、6个C21甾体苷元[11α-O-Tigloyl-12β-O-acetyl tenacigenin B(M-3)、11α-O-Benzoyl-12β-O-acetyl-tenacigenin B(M-4)、11α-O-2-Methylbutanoyl-12β-Otigloyl-tenacigenin B(M-5)、11α-O-2-Methylbutanoyl-12β-O-benzoyl-tenacigenin B(M-9)、11α-O-2-Methylbutanoyl-12β-O-acetyl-tenacigenin B(M-11)和11α,12β-Di-O-tigloyl-tenacigenin B(M-19)]都能明显降低紫杉醇对人宫颈癌细胞He La、人结肠癌细胞HCT-15、人鼻咽癌细胞CNE、人肝癌细胞Hep G2的IC50值,但3个无酯基取代的C21甾体苷元通光散苷元乙(Tenacigenin B,A-1)、17β-通光散苷元乙(17β-Tenacigenin B,A-2)和通光散苷元甲(Tenacigenin A,A-3)无体外化疗增效活性;在HeLa移植瘤裸鼠模型上,通光散苷元M-11和通光散苷M-13能够明显增强紫杉醇对肿瘤的抑制作用。结论通光散中的Tenacigenin B酯类衍生物具有增强紫杉醇的抗肿瘤作用,苷元C-11位和C-12位的酯基取代对其增强抗肿瘤作用必不可少。
Objective To investigate the bioactive components in Chinese herbal material Tongguangsan(Marsdenia tenacissima) which can enhance the antitumor activity of paclitaxel. Methods MTT assay was used for the measurement of IC50value(concentration of inhibiting 50 % of the cell growth)of paclitaxel in the presence or absence of a test compound from Tongguangsan at its non-cytotoxic concentration. Tumor-bearing nude mouse model was used to evaluate tumor-inhibiting effect of paclitaxel alone or in combination with the test compound. Results Five C21 steroidal glycosides and six C21 steroidal aglycones from Tongguangsan had the effect on decreasing IC50 values of paclitaxel for human cervical carcinoma cell line He La, human colorectal cancer cell line HCT-15, human nasopharyngeal cancer cell line CNE and human hepatoma cell line Hep G2, and the 5 C21 steroidal glycosides are tenacissimoside C(M-12), marsdenoside A(M-13), marsdenoside C(M-17), tenacissimoside A(M-18) and tenacissoside E(M-21),and six C21 steroidal aglycones are 11α-O-tigloyl-12β-O-acetyl tenacigenin B(M-3),11α-O-benzoyl-12β-O-acetyl-tenacigenin B(M-4),11α-O-2-methylbutanoyl-12β-O-tigloyl-tenacigenin B(M-5),11α-O-2-methylbutanoyl-12β-O-benzoyl-tenacigenin B(M-9),11α-O-2-Methyl-butanoyl-12β-O-acetyltenacigenin B(M-11),and 11α,12β-di-O-tigloyl-tenacigenin B(M-19). However,tenacigenin B(A-1),17β-tenacigenin B(A-2) and tenacigenin A(A-3) which have no ester group substitution did not show such activity. In He La-tumor- bearing nude mice, an aglycone(M-11) and a glycoside(M-13) were further investigated and the results showed that they both significantly enhanced the inhibitory effect of paclitaxel on tumor growth. Conclusion C21 steroids are the main chemosensitive components from Tongguangsan in enhancing the antitumor activity of paclitaxel,and ester groups on the sites of C-11 and C-12 of aglycone tenacigenin B are required for maintaining the activity of enhancing the antitumor efficacy of paclitaxel.
Objective To investigate the bioactive components in Chinese herbal material Tongguangsan(Marsdenia tenacissima) which can enhance the antitumor activity of paclitaxel. Methods MTT assay was used for the measurement of IC50value(concentration of inhibiting 50 % of the cell growth)of paclitaxel in the presence or absence of a test compound from Tongguangsan at its non-cytotoxic concentration. Tumor-bearing nude mouse model was used to evaluate tumor-inhibiting effect of paclitaxel alone or in combination with the test compound. Results Five C21 steroidal glycosides and six C21 steroidal aglycones from Tongguangsan had the effect on decreasing IC50 values of paclitaxel for human cervical carcinoma cell line He La, human colorectal cancer cell line HCT-15, human nasopharyngeal cancer cell line CNE and human hepatoma cell line Hep G2, and the 5 C21 steroidal glycosides are tenacissimoside C(M-12), marsdenoside A(M-13), marsdenoside C(M-17), tenacissimoside A(M-18) and tenacissoside E(M-21),and six C21 steroidal aglycones are 11α-O-tigloyl-12β-O-acetyl tenacigenin B(M-3),11α-O-benzoyl-12β-O-acetyl-tenacigenin B(M-4),11α-O-2-methylbutanoyl-12β-O-tigloyl-tenacigenin B(M-5),11α-O-2-methylbutanoyl-12β-O-benzoyl-tenacigenin B(M-9),11α-O-2-Methyl-butanoyl-12β-O-acetyltenacigenin B(M-11),and 11α,12β-di-O-tigloyl-tenacigenin B(M-19). However,tenacigenin B(A-1),17β-tenacigenin B(A-2) and tenacigenin A(A-3) which have no ester group substitution did not show such activity. In He La-tumor- bearing nude mice, an aglycone(M-11) and a glycoside(M-13) were further investigated and the results showed that they both significantly enhanced the inhibitory effect of paclitaxel on tumor growth. Conclusion C21 steroids are the main chemosensitive components from Tongguangsan in enhancing the antitumor activity of paclitaxel,and ester groups on the sites of C-11 and C-12 of aglycone tenacigenin B are required for maintaining the activity of enhancing the antitumor efficacy of paclitaxel.
引文
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[17]蒋毅,罗思齐.通关藤中新C21-甾体甙的化学结构研究[J].中国医药工业杂志,1996,27(9):391-395.
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[19]Miyakawa S,Yamaura K,Hayashui K,et al.Five glycosides from the Chinese drug“Tong-Guang-San”:the stems of Marsdenia tenacissima[J].Phytochemistry,1986,25(12):2861-2865.
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[21]Ye B,Yang J,Li J,et al.In vitro and in vivo antitumor activities of tenacissoside C from Marsdenia tenacissima[J].Planta Med,2014,80(1):29-38.
[2]国家中医药管理局《中华本草》编委会.中华本草(第6册)[M].上海:上海科学技术出版社,1998:372.
[3]中华人民共和国国家药品监督管理局药品标准[S].WS-10630(ZD-0630)-2002.
[4]王文玉,周云,张晓菊,等.消癌平注射液联合化疗治疗晚期非小细胞肺癌的临床观察[J].临床肿瘤学杂志,2009,14:936-938.
[5]孙珏,沈建华,朱美华,等.“消癌平”对人肝癌细胞治疗作用的实验研究[J].上海中医药杂志,2000,34(7):12-14.
[6]袁秀英,范忠泽,黄秀英.消癌平注射液治疗14例晚期胃癌的临床观察[J].上海医药,1996,(6):12-13.
[7]Hu YJ,Shen XL,Lu HL,et al.Tenacigenin B derivatives reverse P-glycoprotein-mediated multidrug resistance in Hep G2/Dox cells[J].J Nat Prod,2008,71(6):1049-1051.
[8]Han SY,Zhao MB,Zhuang GB,et al.Marsdenia tenacissima extract restored gefitinib sensitivity in resistant non-small cell lung cancer cells[J].Lung Cancer,2012,75(1):30-37.
[9]Han SY,Zhao HY,Zhou N,et al.Marsdenia tenacissima extract inhibits gefitinib metabolism in vitro by interfering with human hepatic CYP3A4 and CYP2D6 enzymes[J].J Ethnopharmacol,2014,151(1):210-217.
[10]Huang T,Gong WH,Zou CP,et al.Marsdenia tenacissima extract sensitizes MG63 cells to doxorubicin-induced apoptosis[J].Genet Mol Res,2014,13(1):354-362.
[11]Zhu RJ,Shen XL,Dai LL,et al.Total aglycones from Marsdenia tenacissima increases antitumor efficacy of paclitaxel in nude mice[J].Molecules,2014,19(9):13965-13975.
[12]吴斯东,朱瑞静,沈小玲,等.通光散总苷的肿瘤细胞化疗增敏活性与质量控制方法研究[J].分析测试学报,2014,33(10):1199-1203.
[13]Luo SQ,Lin LZ,Cordell GA,et al.Polyoxypregnanes from Marsdenia tenacissima[J].Phytochemistry,1993,34(6):1615-1620.
[14]周俊,杨仁洲,杨崇仁.通光散苷元甲的化学结构[J].植物学报,1980,22(1):67-74.
[15]杨仁洲,杨崇仁,周俊.通光藤甙元甲、乙和丙的结构[J].云南植物研究,1981;3(3):271-278.
[16]Li QF,Wang XL,Ding LS,et al.Polyoxypregnanes from the stems of Marsdenia tenacissima[J].Chin Chem Lett,2007,18(7):831-834.
[17]蒋毅,罗思齐.通关藤中新C21-甾体甙的化学结构研究[J].中国医药工业杂志,1996,27(9):391-395.
[18]Deng J,Liao ZX,Chen DF.Marsdenosides A-H,polyoxypregnane glycosides from Marsdenia tenacissima[J].Phytochem,2005,66(9):1040-1051.
[19]Miyakawa S,Yamaura K,Hayashui K,et al.Five glycosides from the Chinese drug“Tong-Guang-San”:the stems of Marsdenia tenacissima[J].Phytochemistry,1986,25(12):2861-2865.
[20]国家药典委员会.中华人民共和国药典(一部)[M].北京:中国医药科技出版社,2010:277-278.
[21]Ye B,Yang J,Li J,et al.In vitro and in vivo antitumor activities of tenacissoside C from Marsdenia tenacissima[J].Planta Med,2014,80(1):29-38.