title: All trans retinoic acid enhances CDDP-induced apoptosis: modulation of the CDDP effect on cell cycle progression.
abstract: We have previously shown that ATRA potentiates CDDP cytotoxicity in various ovarian carcinoma cell lines. In the present study, we found that the enhanced sensitivity to CDDP was due to an increase of CDDP-induced apoptosis in OVCCR1 and NIH-OVCAR-3 cells. In these cell lines, flow cytometric analysis indicated that CDDP induced an initial accumulation of cells in the S-phase, followed by an increase in the proportion of cells in G2/M phase. Pretreatment of OVCCR1 and NIH-OVCAR-3 cells with ATRA did not modify cell cycle parameters, but delayed S-phase exit of CDDP-treated cells. Bcl-2 over-expression inhibited both delay in S-phase exit and CDDP-induced apoptosis in ATRA-pretreated cells. The CDDP-induced S-phase accumulation of OVCCR1 cells resulted from an activation of CDK2/cyclin A activity. Our results indicate that ATRA-pretreatment modified the CDDP-induced regulation of CDK2 activity by the CDK inhibitors p21 and p27. Taken together, our findings suggest that ATRA potentiates the apoptosis induced by CDDP in ovarian carcinoma cells and that this action is sustained by modulation of the activity of CDK2/cyclin A.
authors.affiliation: Laboratoire d'Histologie-Embryologie, Faculté de Médecine, Toulouse, France. jozan@cict.fr
authors.forename: Suzanne
authors.initials: S
authors.lastname: Jozan
authors.forename: Sebastien
authors.initials: S
authors.lastname: Paute
authors.forename: Monique
authors.initials: M
authors.lastname: Courtade-Saïdi
authors.forename: Severine
authors.initials: S
authors.lastname: Julié
authors.forename: Simone
authors.initials: S
authors.lastname: Vidal
authors.forename: Roland
authors.initials: R
authors.lastname: Bugat
authors.forename: Annie
authors.initials: A
authors.lastname: Valette
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D019925:Cyclin A / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004357:Drug Synergism; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D019925:Cyclin A; D014212:Tretinoin; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D002945:Cisplatin