Department of Obstetrics and Gynecology, Campus Innenstadt, Ludwig-Maximilians-University Munich, Munich, Germany.
Curr Cancer Drug Targets. 2011 Sep;11(7):799-809. doi: 10.2174/156800911796798913.
The occurrence of chemoresistance is a serious problem in the treatment of cancer, urging the need for second and third-line treatment options that rely on different cell death pathways to overcome previously acquired resistance mechanisms. The inhibition of proteasomal activity by specific proteasome inhibitors or cross-reactivity of certain protease inhibitors with proteasomal enzymes recently became of interest because of the anti-tumoral properties of these agents. We tested the proteasome inhibitor bortezomib and the HIV protease inhibitor nelfinavir on human cervical cancer cells. Both drugs induced cell cycle arrest in cervical cancer cells, as reflected by marked changes in the expression of cell cycle-regulatory cyclins and ensuing mitochondrial-independent apoptosis. Upregulation of the molecular chaperone BiP and the cell stress marker ATF3 indicated induction of the unfolded protein response (UPR) as the main cause of apoptosis induced by these drugs in cervical cancer cells. Unlike in leukemia cells, bortezomib mainly inhibited the caspase-like activity of the proteasome in cervical cancer cells. Nelfinavir exhibited no effects on proteasomal activity in cervical cancer cells and leukemia cells. Although both bortezomib and nelfinavir acted on cisplatin-resistant cervical cancer cells (SiHa), neither of the drugs induced a sensitization to cisplatin treatment. Instead, both drugs could effectively be combined with each other, and enhanced the efficacy of an apoptosis-inducing TRAIL receptor antibody. These results suggest that both bortezomib and nelfinavir are effective agents against chemoresistant cervical cancer cells and might be of interest for clinical studies on cervical cancer patients with recurrent or metastatic cancer.
化疗耐药性的发生是癌症治疗中的一个严重问题，这促使人们需要寻找第二和第三线治疗选择，这些选择依赖于不同的细胞死亡途径，以克服先前获得的耐药机制。由于这些药物具有抗肿瘤特性，特异性蛋白酶体抑制剂抑制蛋白酶体活性或某些蛋白酶抑制剂与蛋白酶体酶的交叉反应最近引起了人们的兴趣。我们测试了蛋白酶体抑制剂硼替佐米和 HIV 蛋白酶抑制剂奈非那韦对人宫颈癌细胞的作用。这两种药物都诱导了宫颈癌细胞的细胞周期停滞，这反映在细胞周期调节细胞周期蛋白的表达发生明显变化，并随后发生线粒体非依赖性细胞凋亡。分子伴侣 BiP 和细胞应激标志物 ATF3 的上调表明，这些药物在宫颈癌细胞中诱导细胞凋亡的主要原因是未折叠蛋白反应 (UPR) 的诱导。与白血病细胞不同，硼替佐米主要抑制宫颈癌细胞中蛋白酶体的半胱天冬酶样活性。奈非那韦对宫颈癌细胞和白血病细胞中的蛋白酶体活性没有影响。虽然硼替佐米和奈非那韦都作用于顺铂耐药的宫颈癌细胞 (SiHa)，但这两种药物都没有诱导对顺铂治疗的敏感性。相反，这两种药物可以有效地联合使用，并增强凋亡诱导 TRAIL 受体抗体的疗效。这些结果表明，硼替佐米和奈非那韦都是针对化疗耐药性宫颈癌细胞的有效药物，可能对复发性或转移性宫颈癌患者的临床研究具有重要意义。
