Fang M, Liu B, Schmidt M, Lu Y, Mendelsohn J, Fan Z
Department of Clinical Investigation, University of Texas M.D. Anderson Cancer Center, Houston, USA.
Anticancer Res. 2000 Jan-Feb;20(1A):103-11.
Paclitaxel (Taxol) is currently one of the most widely used anti-cancer drugs for human breast cancer. In this study, we investigated how epidermal growth factor (EGF) modulated paclitaxel-induced apoptosis in MDA-MB-468 human breast adenocarcinoma cells. Pulse-exposure of the cells to paclitaxel resulted in cell death through apoptosis. When EGF was present during the post-paclitaxel culture period, this paclitaxel-induced apoptosis was inhibited in an EGF dose-dependent manner. The induction of apoptosis by paclitaxel was accompanied by an elevated level of p34cdc2 kinase activity, which was inhibited in the presence of EGF during the post-paclitaxel culture period. Exposure of MDA-MB-468 cells to EGF induced expression of the cyclin-dependent kinase inhibitor p21Waf1. Incubation of paclitaxel-treated MDA-MB-468 cell extracts with EGF-treated MDA-MB-468 cell extract, which exhibited elevation of p34cdc2 activity, inhibited the kinase activity. This inhibition was not observed with p21Waf1-immunodepleted EGF-treated cell extract. Transfection of the cells with p21Waf1 antisense oligonucleotide abolished the induction of p21Waf1 and also significantly reduced inhibition by EGF of paclitaxel-induced apoptosis. These studies demonstrate that p21Waf1 plays a key role in the inhibition of paclitaxel-induced apoptosis by EGF in MDA-MB-468 cells.
紫杉醇（泰素）是目前治疗人类乳腺癌应用最广泛的抗癌药物之一。在本研究中，我们调查了表皮生长因子（EGF）如何调节紫杉醇诱导的MDA-MB-468人乳腺腺癌细胞凋亡。细胞脉冲暴露于紫杉醇会导致细胞通过凋亡死亡。当在紫杉醇培养期后加入EGF时，这种紫杉醇诱导的凋亡会以EGF剂量依赖的方式受到抑制。紫杉醇诱导凋亡伴随着p34cdc2激酶活性升高，在紫杉醇培养期后加入EGF时，该活性受到抑制。MDA-MB-468细胞暴露于EGF会诱导细胞周期蛋白依赖性激酶抑制剂p21Waf1的表达。用EGF处理过的MDA-MB-468细胞提取物（其p34cdc2活性升高）与紫杉醇处理过的MDA-MB-468细胞提取物共同孵育，会抑制激酶活性。用p21Waf1免疫耗尽的EGF处理过的细胞提取物未观察到这种抑制作用。用p21Waf1反义寡核苷酸转染细胞消除了p21Waf1的诱导，并且也显著降低了EGF对紫杉醇诱导凋亡的抑制作用。这些研究表明，p21Waf1在EGF抑制MDA-MB-468细胞中紫杉醇诱导的凋亡过程中起关键作用。
