Nelfinavir induces liposarcoma apoptosis and cell cycle arrest by upregulating sterol regulatory element binding protein-1.

Abstract

"HIV protease-induced lipodystrophy syndrome" is associated with the use of HIV protease inhibitors for treatment of HIV infection. In-vitro studies suggest that alteration of sterol regulatory element binding protein-1 levels underlie its pathogenesis. We postulated that HIV protease inhibitors may represent a novel class of antiliposarcoma agents. SW872, FU-DDLS-1 and LiSa-2 liposarcoma, and HT1080 and 293 nonliposarcoma cell lines were treated with HIV protease inhibitors (nelfinavir, ritonavir, saquinavir, indinavir and amprenavir), and clonogenic assays were performed. Nelfinavir exhibited the most potent inhibition of clonogenicity, and further assays for proliferation, cell cycle and apoptosis were performed with nelfinavir. Immunoblots were performed for sterol regulatory element binding protein-1, proapoptotic and cell cycle-related protein expression after nelfinavir treatment. Finally, a sterol regulatory element binding protein-1-inducible SW872 cell line was developed to examine the phenotype resulting from upregulated sterol regulatory element binding protein-1. Nelfinavir selectively inhibited clonogenicity and proliferation, and induced G1 cell cycle block and induced apoptosis in a dose-dependent manner in SW872 and LiSa-2 cells, whereas it had minimal or no effect on these parameters in FU-DDLS-1 or nonliposarcoma cells. Nelfinavir induced significant sterol regulatory element binding protein-1 expression in a dose-dependent and time-dependent fashion in sensitive SW872 and LiSa-2 cells, modestly in HT1080 cells, but not in nelfinavir-insensitive FU-DDLS-1 and 293 cells without inducing adipocytic differentiation. Forced expression of sterol regulatory element binding protein-1 in inducible-SW872 cells led to the induction of proapoptotic and antiproliferative proteins, and consequent reduction of cellular proliferation. Our data indicate that nelfinavir represents a novel class of antiliposarcoma agent that acts by selectively upregulating sterol regulatory element binding protein-1 expression in liposarcomas.

• Authors: Warren A Chow, Song Guo, Frances Valdes-Albini
• Journal: Anti-cancer drugs (Anticancer Drugs) Vol. 17 Issue 8 Pg. 891-903 (Sep 2006) ISSN: 0959-4973 [Print] England
• PMID: 16940799 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• BAX protein, human
• CDKN1A protein, human
• Cyclin-Dependent Kinase Inhibitor p21
• FAS protein, human
• HIV Protease Inhibitors
• Sterol Regulatory Element Binding Protein 1
• Tumor Suppressor Protein p53
• bcl-2-Associated X Protein
• fas Receptor
• Nelfinavir

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
• Dose-Response Relationship, Drug
• HIV Protease Inhibitors (pharmacology)
• Humans
• Liposarcoma (metabolism, pathology)
• Nelfinavir (pharmacology)
• Sterol Regulatory Element Binding Protein 1 (genetics, metabolism)
• Tumor Suppressor Protein p53 (metabolism)
• Up-Regulation (drug effects)
• bcl-2-Associated X Protein (metabolism)
• fas Receptor (metabolism)