Nelfinavir induces necrosis of 3T3F44-2A adipocytes by oxidative stress.
Protease inhibitor treatment strongly diminishes mortality in HIV-infected patients. This treatment has also been associated with lipodystrophy and has been shown to alter adipocyte differentiation. The protease inhibitor nelfinavir has been indirectly implicated in the appearance and development of lipodystrophic syndrome, as well as in adipocyte cell death. The aim of this study was to evaluate the effects of nelfinavir on the 3T3-F442A adipocyte cell line. Nelfinavir (30 microM) induced cell death of 3T3-F442A adipocytes by a necrotic process that was not mediated by TNF-alpha. Treatment of cells with this protease inhibitor led to a significant increase in expression of the heme oxygenase-1 gene that could be reduced by 100 microM of the antioxidant ascorbate. Moreover, ascorbate had a protective effect on nelfinavir-induced necrosis, decreasing the percentage of necrotic cells by 70%. Our results show that nelfinavir induces necrosis of adipocytes mediated by a cellular increase of reactive oxygen species. This deleterious effect could be counterbalanced by ascorbate.
Vincent
Stéphanie
S
INSERM 476 Unit, School of Medicine, Marseille, France.
Tourniaire
Franck
F
El Yazidi
Claire M
CM
Compe
Emmanuel
E
Manches
Olivier
O
Plannels
Richard
R
Roche
Régis
R
D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D017209:Apoptosis; D001205:Ascorbic Acid / Q000494:pharmacology; D002460:Cell Line; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009336:Necrosis / Q000139:chemically induced*; D019888:Nelfinavir / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*
D017320:HIV Protease Inhibitors; D051547:Heme Oxygenase-1; D019888:Nelfinavir; D001205:Ascorbic Acid