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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 displays atypical multidrug resistance, is presented. A2780‐DX3 is found to be more resistant than the parental line A2780 in terms of CDDP‐induced cytotoxicity and apoptosis. Resistance is not related to the amount of cross‐links. Topoisomerase‐II (topII) protein levels were similar 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 resistance. bcl2 was almost undetectable in both cell lines. At the same time, we found strong induction of p53, waf‐1 and bax protein levels after CDDP treatment in the A2780, but not in the A2780‐DX3, cell line. Treatment of both cell lines with mitomycin C (MMC), which acts with a mechanism different from CDDP, caused equal accumulation of p53 and induction of bax. We found that A2780‐DX3 cells exhibit altered cellular localization of p53 protein in comparison with A2780. A significant proportion of p53 in A2780‐DX3 cells was found in the cytoplasmic compartment, and CDDP 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 due to inactivation of a CDDP‐dependent p53‐accumulation pathway. Int. J. Cancer 72:155–159, 1997. © 1997 Wiley‐Liss Inc.