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Mechanisms of sulindac-induced apoptosis and cell cycle arrest

Barbara Jung1, Valerie Barbier, Howard Brickner

  • 1Department of Molecular Biology, Sidney Kimmel Cancer Center, 10835 Altman Row, San Diego, CA 92121, USA. bjung@ucsd.edu

Cancer Letters
|February 8, 2005
PubMed

Insights

The non-steroidal anti-inflammatory drug sulindac and its metabolite sulindac sulfide induce cell death independently of p53 and Fas pathways. Sulindac sulfide targets premalignant cells with cell cycle deficits.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Pharmacology

Background:

  • The chemopreventive mechanisms of sulindac, a non-steroidal anti-inflammatory drug, are not fully understood.
  • Sulindac sulfide, an active metabolite, induces apoptosis and cell cycle arrest in cancer cells.

Purpose of the Study:

  • To elucidate the molecular mechanisms of sulindac sulfide-induced cell death.
  • To investigate the role of p53, Fas, and cell cycle regulators in sulindac sulfide's effects.

Main Methods:

  • Murine thymocytes and mouse embryonic fibroblasts (MEFs) were used to study cell death and cell cycle arrest.
  • Experiments involved wild-type, bcl2 transgenic, p21-deficient, and Rb-deficient cells.

Main Results:

  • Sulindac sulfide-induced thymocyte death was independent of p53, Bax, Fas, and FasL.
  • Thymocytes overexpressing bcl2 were resistant to sulindac sulfide-induced apoptosis.
  • Cell cycle arrest in MEFs was partly mediated by retinoblastoma protein (Rb) and p21waf1/cip1.
  • MEFs deficient in p21 or Rb showed increased susceptibility to sulindac sulfide-induced cell death.

Conclusions:

  • Sulindac sulfide induces cell death through p53/Fas-independent pathways.
  • The retinoblastoma (Rb) and p21 pathways are involved in sulindac sulfide-induced cell cycle arrest.
  • Sulindac may selectively target premalignant cells with compromised cell cycle checkpoints.

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