Wu Zhen, Wu Lijun, Li Linhao, Tashiro Shin-Ichi, Onodera Satoshi, Ikejima Takashi
Department of Phytochemistry, Shenyang Pharmaceutical University, P.R. China.
J Pharmacol Sci. 2004 Feb;94(2):166-76. doi: 10.1254/jphs.94.166.
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.
天然产物可响应致癌基因激活调节细胞生长，致癌基因激活会诱导肿瘤细胞系中的细胞周期停滞和凋亡。我们研究了从植物紫草（Lithospermum erythrorhizon SIEB. et ZUCC.）中分离出的天然产物紫草素在人恶性黑色素瘤A375-S2细胞中激活半胱天冬酶的机制。紫草素以时间和剂量依赖性方式抑制细胞生长，这可能是通过上调p53和下调细胞周期蛋白依赖性蛋白激酶4介导的。在紫草素诱导的细胞凋亡中检测到半胱天冬酶激活，其涉及线粒体后半胱天冬酶-9依赖性途径。Bcl-2蛋白水平降低和Bax蛋白水平升高与p53蛋白表达升高呈正相关。凋亡诱导因子是线粒体的另一种凋亡蛋白，部分促成了紫草素诱导的细胞色素c释放。综上所述，紫草素诱导的DNA损伤激活了p53和半胱天冬酶-9途径。
