A role for loss of p53 function in sensitivity of ovarian carcinoma cells to taxanes

Loss of p53 function has been linked to increased responsiveness to taxane treatment of ovarian carcinoma in clinical studies. We recently reported th at the acquisition of cisplatin resistance in an ovarian carcinoma cell lin e (IGROV-I) was associated with mutation of p53 and collateral sensitivity to paclitaxel, The increased sensitivity to paclitaxel of the cisplatin-res istant subline appeared to be pharmacologically relevant since it was refle cted in an in vivo sensitization to taxanes, To investigate the cellular an d molecular basis of this phenomenon, we performed a comparative study of c ellular response to taxanes (paclitaxel and the novel analog IDN 5109) in t he parental cell line, containing wild-type p53 and its cisplatin-resistant p53 mutant subline (IGROV-I/PtI), IDN 5109 was included in this study beca use of its higher potency and efficacy compared with paclitaxel on both tum or systems. The pattern of cellular response of the two ovarian cell lines was different. in IGROV-I cells, apoptosis was an early event consequent to a transient mitotic arrest. The cell death of IGROV-I/PtI cells was a some what slow and delayed event, following mitotic arrest and appearance of hyp erploid cells. The increased cytotoxic effect of IDN 5109, compared with pa clitaxel, was associated with more marked p34(cdc2) dephosphorylation in IG ROV-I cells and higher Bcl-2 phosphorylation in IGROV-I/PtI cells after 24 hr of treatment. In each cell line, these biochemical events were not corre lated with parallel levels of mitotic cells. Attempts to reintroduce wild-t ype p53 in IGROV-I/PtI[ were unsuccessful, However, in other p53-deficient cells (osteosarcoma SAGS), taxane treatment was associated with hyperploid progression and the introduction of wild-type p53 resulted in a reduced sen sivity, Although our approach does not allow definitive conclusions, these results suggest that loss of p53-dependent post-mitotic checkpoint results in a different time-course of taxane-induced cell death following DNA redup lication. These events, more evident after exposure to the potent analog ID N 5109, support the notion that the Enhanced sensitivity of p53 mutant cell s is closely related to the different mode of cell death. (C) 2001 Wiley-Li ss, Inc.