Karl Theresia, Seibert Nadine, Stöhr Michael, Osswald Hans, Rösl Frank, Finzer Patrick
Deutsches Krebsforschungszentrum, Forschungsschwerpunkt Angewandte Tumorvirologie, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
Cancer Lett. 2007 Jan 8;245(1-2):103-11. doi: 10.1016/j.canlet.2005.12.034. Epub 2006 Feb 20.
Sulindac, a nonsteroidal anti-inflammatory drug (NSAID), induces growth arrest in HeLa cells and causes strong inhibition of the G1 to S transition of the cell cycle in a concentration-dependent manner. The G1 arrest is preceded by suppression of cyclin E and A, inactivation of cdk2, and the complete loss of the viral oncoprotein E7, despite ongoing HPV transcription. As shown by inhibitors specific for cyclooxygenase (COX) 1 and 2 loss of E7 is COX-independent. Moreover, inhibition of the proteasome activity with MG132 partially blocked the ability of sulindac to suppress E7 suggesting that sulindac induces degradation of E7 by the proteasomal pathway. In addition to inhibiting growth, sulindac strongly induces apoptosis, which can be abrogated by using the general caspase inhibitor zVAD-fmk. Unchanged expression of the pro-apoptotic protein Bax and suppression of the anti-apoptotic molecules Bcl-2 and Bcl-x(L) argues for the engagement of the mitochondrial apoptotic pathway. These results support the notion that sulindac is a potent growth inhibitor and inducer of apoptosis on cervical cancer cells in vitro and may offer new perspectives as a chemopreventive or supplementary anti-cervical cancer drug.
舒林酸是一种非甾体抗炎药（NSAID），可诱导HeLa细胞生长停滞，并以浓度依赖的方式强烈抑制细胞周期从G1期到S期的转变。在G1期停滞之前，细胞周期蛋白E和A受到抑制，细胞周期蛋白依赖性激酶2（cdk2）失活，病毒癌蛋白E7完全丧失，尽管人乳头瘤病毒（HPV）仍在转录。如环氧合酶（COX）1和2特异性抑制剂所示，E7的丧失与COX无关。此外，用MG132抑制蛋白酶体活性部分阻断了舒林酸抑制E7的能力，这表明舒林酸通过蛋白酶体途径诱导E7降解。除了抑制生长外，舒林酸还强烈诱导细胞凋亡，使用通用的半胱天冬酶抑制剂zVAD-fmk可消除这种凋亡。促凋亡蛋白Bax表达未改变，抗凋亡分子Bcl-2和Bcl-x(L)受到抑制，这表明线粒体凋亡途径被激活。这些结果支持了这样一种观点，即舒林酸在体外是一种有效的宫颈癌细胞生长抑制剂和凋亡诱导剂，可能为化学预防或辅助抗宫颈癌药物提供新的视角。
