Induction of apoptosis by taxol and cisplatin and effect on cell cycle-related proteins in cisplatin-sensitive and -resistant human ovarian cancer cells
Induction of apoptosis by taxol and cisplatin and effect on cell cycle-related proteins in cisplatin-sensitive and -resistant human ovarian cancer cells
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DOI：
10.1038/bjc.1998.230
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发表时间：
1998-05-01
影响因子：
8.8
通讯作者：
Villa, R
中科院分区：
文献类型：
--
作者：
Zaffaroni, N;Silvestrini, R;Villa, R
本研究观察了紫杉醇（TX）和顺铂（CDDP）单独或联合应用对两种人卵巢癌细胞系（A2780和A2780 cp 8）的作用。细胞系显示出类似的敏感性，TX，而不同的细胞毒性结果中得到的两个细胞系作为TX和CDDP序列的函数。具体而言，TX后接CDDP在两种细胞系中诱导简单的累加效应。而相反序列在A2780细胞中产生拮抗作用，在A2780 cp 8细胞中产生协同作用。TX，有或没有CDDP，诱导寡核小体DNA片段典型的凋亡过程中，但发生凋亡的生化机制是不同的两个细胞系。事实上，在A2780细胞中，TX（有或没有CDDP）处理显著增加p53以及p21（waf 1）蛋白表达。在A2780 cp 8细胞中，药物处理增强了p53的水平，而p21（waf 1）的表达在mRNA和蛋白水平上总是检测不到。在后一种细胞系中，观察到p34（cdc 2）激酶的过早激活与药物诱导的S期细胞分数增加相对应。这种激活并不归因于p34（cdc 2）或细胞周期蛋白B-1蛋白的总体表达的增加，而是归因于p34（cdc 2）激酶的去磷酸化。总的来说，我们的研究结果表明，TX诱导的人卵巢癌细胞凋亡可能是由细胞周期控制水平的不同事件维持的。
The effect of taxol (TX) and cisplatin (CDDP), singly or in association, was assessed on two human ovarian cancer cell lines, one sensitive (A2780) and one resistant (A2780 cp8) to CDDP. Cell lines showed a similar sensitivity to TX, whereas different cytotoxicity results were obtained in the two cell lines as a function of TX and CDDP sequence. Specifically, TX followed by CDDP induced simply additive effects in both cell lines. whereas the opposite sequence produced antagonistic effects in A2780 cells and synergistic effects in A2780 cp8 cells. TX, with or without CDDP, induced oligonucleosomal DNA fragmentation typical of the apoptotic process, but the biochemical mechanisms undergoing apoptosis were different in the two cell lines. In fact, in A2780 cells, TX (with or without CDDP) treatment markedly increased p53 as well as p21(waf1) protein expression. In A2780 cp8 cells, drug treatment enhanced p53 levels, whereas the expression of p21(waf1) was always undetectable at mRNA and protein levels. In the latter cell line, a premature activation of p34(cdc2) kinase was observed in correspondence with the drug-induced increase in the S-phase cell fraction. Such an activation was not ascribable to an increase in the overall expression of p34(cdc2) or cyclin B-1 proteins, but to a dephosphorylation of p34(cdc2) kinase. Overall, our results indicate that TX-induced apoptosis in human ovarian cancer cells may be sustained by different events at the cell cycle-control level.