Mechanisms of sulindac-induced apoptosis and cell cycle arrest.
The mechanism underlying the chemopreventive effects of the non-steroidal anti-inflammatory drug sulindac remains unclear. Its active metabolite, sulindac sulfide, induces cell cycle arrest as well as apoptosis in mammalian cell lines. We now show that in murine thymocytes, sulindac sulfide-induced cell death is p53, bax, Fas, and FasL independent. In contrast, bcl2 transgenic thymocytes are resistant to sulindac sulfide-induced apoptosis. In addition, we demonstrate that sulindac sulfide-induced cell cycle arrest in mouse embryonic fibroblasts (MEFs) is partly mediated by the retinoblastoma tumor suppressor protein (Rb) and the cyclin kinase inhibitor p21waf1/cip1. Furthermore, MEFs deficient in p21 or Rb are more susceptible to sulindac sulfide-induced cell death. These results suggest that sulindac may selectively target premalignant cells with cell cycle checkpoint deficits.
Jung
Barbara
B
Department of Molecular Biology, Sidney Kimmel Cancer Center, 10835 Altman Row, San Diego, CA 92121, USA. bjung@ucsd.edu
Barbier
Valerie
V
Brickner
Howard
H
Welsh
John
J
Fotedar
Arun
A
McClelland
Michael
M
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D051379:Mice; D008822:Mice, Transgenic; D016160:Retinoblastoma Protein / Q000187:drug effects / Q000378:metabolism*; D013467:Sulindac / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism
D000970:Antineoplastic Agents; C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016160:Retinoblastoma Protein; D013467:Sulindac