p53-mediated cell cycle arrest and apoptosis induced by shikonin via a caspase-9-dependent mechanism in human malignant melanoma A375-S2 cells

被引:104
作者
Wu, Z
Wu, LJ
Li, LH
Tashiro, S
Onodera, S
Ikejima, T
机构
[1] Shenyang Pharmaceut Univ, China Japan Res Inst Med & Pharmaceut Sci, Shenyang 110016, Peoples R China
[2] Showa Pharmaceut Univ, Dept Clin & Biomed Sci, Machida, Tokyo 1948543, Japan
关键词
shikonin; cell cycle arrest; apoptosis; caspase; p53;
D O I
10.1254/jphs.94.166
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Natural products regulate cell growth in response to oncogene activation that induces cell cycle arrest and apoptosis in tumor cell lines. We investigated the mechanisms of caspase activation in human malignant melanoma, A375-S2 cells, by the natural product shikonin, which was isolated from the plant Lithospermum erythrorhizon SIEB. et ZUCC. Shikonin inhibited cell growth in a time- and dose-dependent manner, which might be mediated through up-regulation of p53 and down-regulation of cyclin-dependent protein kinase 4. Caspase activation was detected in shikonin-induced cell apoptosis, which involved in a post-mitochondrial caspase-9-dependent pathway. Decreased Bcl-2 protein levels and increased Bax protein levels were positively correlated with elevated expression of p53 protein. Apoptosis-inducing factor, another apoptotic protein of mitochondria, partially contributed to shikonin-induced release of cytochrome c. Taken together, shikonin-induced DNA damage activates p53 and caspase-9 pathways.
引用
收藏
页码:166 / 176
页数:11
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