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Nelfinavir induces mitochondria protection by ERK1/2-mediated mcl-1 stabilization that can be overcome by sorafenib

Ansgar Brüning1, Petra Burger, Marianne Vogel

  • 1Department of Obstetrics/Gynaecology, Molecular Biology Laboratory, Ludwig-Maximilians University Munich, Munich, Germany. ansgar231@web.de

Investigational New Drugs
|June 26, 2009
PubMed

Insights

The HIV drug nelfinavir induces cancer cell death, but increases anti-apoptotic protein mcl-1. Combining nelfinavir with sorafenib blocks this effect, enhancing cancer cell apoptosis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Nelfinavir, an HIV protease inhibitor, shows potential as an anti-cancer therapeutic.
  • Nelfinavir induces apoptosis in chemo-resistant ovarian cancer cells.
  • Nelfinavir upregulates the anti-apoptotic protein mcl-1, impacting its apoptotic effects.

Purpose of the Study:

  • To investigate the mechanism of nelfinavir-induced apoptosis in ovarian cancer.
  • To explore the role of mcl-1 and ERK1/2 signaling in nelfinavir's action.
  • To evaluate the efficacy of combining nelfinavir with sorafenib.

Main Methods:

  • Assessing apoptosis induction by nelfinavir in ovarian cancer cells.
  • Analyzing mcl-1 and ERK1/2 phosphorylation levels.
  • Evaluating the combination therapy of nelfinavir and sorafenib.

Main Results:

  • Nelfinavir upregulates mcl-1 via ERK1/2 phosphorylation, affecting apoptosis.
  • Sorafenib inhibits nelfinavir-induced ERK1/2 activation and mcl-1 upregulation.
  • The combination therapy disrupts mitochondrial membrane potential and enhances nelfinavir's anti-cancer activity.

Conclusions:

  • Nelfinavir's anti-cancer effect is modulated by mcl-1 and ERK1/2 signaling.
  • Combining nelfinavir with sorafenib offers a novel strategy for overcoming chemo-resistance.
  • This combination therapy presents a promising approach for treating ovarian cancer.

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