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

Warren A. Chow, Song Guo, Frances Valdes

Research output: Contribution to journalArticle

26 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)891-903
Number of pages13
JournalAnti-Cancer Drugs
Volume17
Issue number8
DOIs
StatePublished - Sep 1 2006
Externally publishedYes

Fingerprint

Nelfinavir
Sterol Regulatory Element Binding Protein 1
Liposarcoma
Cell Cycle Checkpoints
Apoptosis
HIV Protease Inhibitors
Cell Cycle
Saquinavir
HIV Protease
Indinavir
Lipodystrophy
Cell Line
Ritonavir
Cell Cycle Proteins
HIV Infections
Cell Proliferation
Phenotype

Keywords

  • Liposarcoma
  • Nelfinavir
  • Sterol regulatory element binding protein-1

ASJC Scopus subject areas

  • Pharmacology
  • Cancer Research
  • Oncology

Cite this

Nelfinavir induces liposarcoma apoptosis and cell cycle arrest by upregulating sterol regulatory element binding protein-1. / Chow, Warren A.; Guo, Song; Valdes, Frances.

In: Anti-Cancer Drugs, Vol. 17, No. 8, 01.09.2006, p. 891-903.

Research output: Contribution to journalArticle

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