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.
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Authors | Ansgar Brüning, Petra Burger, Marianne Vogel, Andrea Gingelmaier, Klaus Friese, Alexander Burges |
Journal | Investigational new drugs
(Invest New Drugs)
Vol. 28
Issue 5
Pg. 535-42
(Oct 2010)
ISSN: 1573-0646 [Electronic] United States |
PMID | 19554262
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Annexin A5
- Antineoplastic Agents
- Benzenesulfonates
- HIV Protease Inhibitors
- Myeloid Cell Leukemia Sequence 1 Protein
- Phenylurea Compounds
- Proto-Oncogene Proteins c-bcl-2
- Pyridines
- Niacinamide
- Propidium
- Sorafenib
- Extracellular Signal-Regulated MAP Kinases
- Nelfinavir
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Topics |
- Annexin A5
(metabolism)
- Antineoplastic Agents
(pharmacology)
- Benzenesulfonates
(pharmacology)
- Cell Death
(drug effects)
- Cell Line, Tumor
- Drug Synergism
- Extracellular Signal-Regulated MAP Kinases
(metabolism)
- Female
- HIV Protease Inhibitors
(pharmacology)
- Humans
- Membrane Potential, Mitochondrial
(drug effects)
- Mitochondria
(drug effects, metabolism)
- Myeloid Cell Leukemia Sequence 1 Protein
- Nelfinavir
(pharmacology)
- Niacinamide
(analogs & derivatives)
- Ovarian Neoplasms
(enzymology, pathology)
- Phenylurea Compounds
- Phosphorylation
(drug effects)
- Propidium
(metabolism)
- Protein Stability
(drug effects)
- Proto-Oncogene Proteins c-bcl-2
(metabolism)
- Pyridines
(pharmacology)
- Sorafenib
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