Dulxanthone A induces cell cycle arrest and apoptosis via up-regulation of p53 through mitochondrial pathway in HepG2 cells
Dulxanthone A induces cell cycle arrest and apoptosis via up-regulation of p53 through mitochondrial pathway in HepG2 cells
复制标题
DOI：
10.1002/ijc.23048
复制
发表时间：
2008-01-01
影响因子：
6.4
通讯作者：
Kohane, Isaac S.
中科院分区：
文献类型：
--
作者：
Tian, Ze;Shen, Jie;Kohane, Isaac S.
植物源天然产物为开发新型抗肿瘤药物提供了丰富的资源。通过生物活性定向分离，发现杜松酮A是一种具有细胞毒性的活性成分。阐明dulxanthone A的细胞毒性机制的研究表明，dulxanthone A始终诱导S期阻滞和凋亡的最敏感的细胞系HepG 2。此外，p53显著上调，导致dulxanthone A处理后下游蛋白质的表达改变。细胞周期相关蛋白cyclin A、cyclin B、cyclin E、cdc-2、p21和p27表达下调。一些与凋亡相关的蛋白质在药物处理后也发生了变化。Bcl-2家族成员Bcl-2和Bax表达下调，而Bcl-2家族成员Bax A表达上调。Bax/Bcl-2的表达比例增加。这导致细胞色素C从线粒体释放到细胞质中。同时，用dulxanthone A刺激Apaf-1与p53。结果，细胞色素C、Apaf-1和半胱天冬酶原-9形成一个溶酶体，这反过来又触发了半胱天冬酶-9、半胱天冬酶-3和下游半胱天冬酶底物的活化。核纤层蛋白A/C和PARP分别下调或裂解。此外，siRNA敲低p53可显著抑制dulxanthone A诱导的HepG 2细胞周期阻滞和凋亡。综上所述，杜松酮A是G. cowa。它在较低浓度下诱导细胞周期停滞，并在较高浓度下通过内在线粒体途径上调HepG 2细胞中的p53来触发细胞凋亡。因此，杜松酮A可能是一个有前途的预防和/或治疗药物对肝癌。(C)2007 Wiley-Liss，Inc.
Natural products derived from plants provide a rich source for development of new anticancer drugs. Dulxanthone A was found to be an active cytotoxic component in Garcinia cowa by bioactivity-directed isolation. Studies to elucidate the cytotoxic mechanisms of dulxanthone A showed that dulxanthone A consistently induced S phase arrest and apoptosis in the most sensitive cell line HepG2. Furthermore, p53 was dramatically up-regulated, leading to altered expression of downstream proteins upon dulxanthone A treatment. Cell cycle related proteins, such as cyclin A, cyclin B, cyclin E, cdc-2, p21 and p27 were down-regulated. Some apoptosis correlated proteins were also altered following the drug treatment. Bcl-2 family members PUMA was up-regulated while Bcl-2 and Bax were down-regulated. However, the expression ratio of Bax/Bcl-2 was increased. This resulted in the release of cytochrome C from the mitochondria to the cytosol. Concurrently, Apaf-1 was stimulated with p53 by dulxanthone A. In result, cytochrome C, Apaf-1 and procaspase-9 form an apoptosome, which in turn triggered the activation of caspase-9, caspase-3 and downstream caspase substrates. Lamin A/C and PARP were down-regulated or cleaved, respectively. Moreover, cell cycle arrest and apoptosis in HepG2 cells induced by dulxanthone A were markedly inhibited by siRNA knockdown of p53. In summary, dulxanthone A is an active cytotoxic component of G. cowa. It induces cell cycle arrest at lower concentrations and triggers apoptosis at higher concentrations via up-regulation of p53 through the intrinsic mitochondrial pathway in HepG2 cells. Dulxanthone A is therefore likely a promising preventive and/or therapeutic agent against Hepatoma. (C) 2007 Wiley-Liss, Inc.