| Title | Nelfinavir induces mitochondria protection by ERK1/2-mediated mcl-1 stabilization that can be overcome by sorafenib. | | Author(s) | Brüning A, Burger P, Vogel M, Gingelmaier A, Friese K, Burges A | | Institution | Department of Obstetrics/Gynaecology, Molecular Biology Laboratory, Ludwig-Maximilians University Munich, Munich, Germany, ansgar231@web.de. | | Source | Invest New Drugs 2009 Jun 26. | | Abstract | 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. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19554262 |
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