MECHANISM OF RESISTANCE TO CISPLATIN IN A HUMAN OVARIAN-CARCINOMA CELL-LINE SELECTED FOR RESISTANCE TO DOXORUBICIN - POSSIBLE ROLE OF P53

A possible novel mechanism of cross-resistance to cisplatin (CDDP) in the doxorubicin-resistant ovarian-cancer cell line A2780-DX3, which di splays atypical multidrug resistance, is presented. A2780-DX3 is found to be more resistant than the parental line A2780 in terms of CDDP-in duced cytotoxicity and apoptosis. Resistance is not related to the amo unt of cross-links. Topoisomerase-II (topII) protein levels were simil ar in both cell lines, with lower cleavage activity in A2780-DX3 cells , The parental and the doxorubicin-resistant cells expressed the same level of c-erb2, which could be implicated in CDDP vesistance. bcl2 wa s almost undetectable in both cell lines. At the same time, we found s trong induction of p53, waf-1 and bar protein levels after CDDP treatm ent in the A2780, but not in the A2780-DX3, cell line, Treatment of bo th cell lines with mitomycin C (MMC), which acts with a mechanism diff erent from CDDP, caused equal accumulation of p53 and induction of bar . We found that A2780-DX3 cells exhibit altered cellular localization of p53 protein in comparison with A2780. A significant proportion of p 53 in A2780-DX3 cells was found in the cytoplasmic compartment, and CD DP treatment induced a functional p53 protein in the nucleus of A2780 much more strongly than in A2780-DX3, which coincides with an increase of transcriptional activity of p53 in treated A2780 cells, We propose that the cross-resistance to CDDP in the A2780-DX3 cell line may be d ue to inactivation of a CDDP-dependent p53-accumulation pathway. (C) 1 997 Wiley-Liss, Inc.