Department of Obstetrics/Gynaecology, Molecular Biology Laboratory, Ludwig-Maximilians University Munich, Munich, Germany.
Invest New Drugs. 2010 Oct;28(5):535-42. doi: 10.1007/s10637-009-9281-1. Epub 2009 Jun 26.
The HIV protease inhibitor nelfinavir is an investigational drug for cancer treatment. We have previously demonstrated induction of apoptosis by nelfinavir even in chemo-resistant ovarian cancer cells. In contrast to the pro-apoptotic effect of nelfinavir on human cancer cells, we noticed a significant upregulation of the anti-apoptotic mitochondrial membrane protein mcl-1 by nelfinavir, resulting in a mitochondria-independent induction of apoptosis. Upregulation of mcl-1 was associated with enhanced phosphorylation of both mcl-1 and of ERK1/2 (extracellular signal-regulated kinases 1/2). ERK1/2 enhanced stability of mcl-1 protein expression by serine-163 phosphorylation. The combination of nelfinavir with sorafenib, a clinically applied inhibitor of the RAS/RAF/ERK1/2 pathway, inhibited nelfinavir-induced ERK1/2 activation and mcl-1 protein upregulation. Further, the combination of nelfinavir with sorafenib induced mitochondrial membrane potential disruption and resulted in an improved activity of nelfinavir on ovarian cancer cells. Thus, a combination of these two investigational anti-cancer drugs could be of interest especially because of their unique mechanism of apoptosis induction even in otherwise chemo-resistant human cancer cells.
HIV 蛋白酶抑制剂奈非那韦是一种用于癌症治疗的研究药物。我们之前已经证明，奈非那韦甚至可以诱导化疗耐药的卵巢癌细胞凋亡。与奈非那韦对人类癌细胞的促凋亡作用相反，我们注意到奈非那韦显著上调了抗凋亡的线粒体膜蛋白 mcl-1，导致线粒体非依赖性的凋亡诱导。mcl-1 的上调与 mcl-1 和 ERK1/2（细胞外信号调节激酶 1/2）的磷酸化增强有关。ERK1/2 通过丝氨酸 163 磷酸化增强了 mcl-1 蛋白表达的稳定性。奈非那韦与索拉非尼（一种临床应用的 RAS/RAF/ERK1/2 通路抑制剂）联合使用，抑制了奈非那韦诱导的 ERK1/2 激活和 mcl-1 蛋白上调。此外，奈非那韦与索拉非尼的联合使用导致线粒体膜电位破坏，并提高了奈非那韦对卵巢癌细胞的活性。因此，这两种研究性抗癌药物的联合使用可能具有重要意义，特别是因为它们具有独特的凋亡诱导机制，即使在其他化疗耐药的人类癌细胞中也是如此。
