Mechanism of resistance to cisplatin in a human ovarian-carcinoma cell line selected for resistance to doxorubicin: Possible role of p53

Faina Vikhanskaya, Luana Clerico, Monica Valenti, Maria S. Stanzione, Massimo Broggini, Silvio Parodi, Patrizia Russo

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Abstract

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-I 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.

Original languageEnglish
Pages (from-to)155-159
Number of pages5
JournalInternational Journal of Cancer
Volume72
Issue number1
DOIs
Publication statusPublished - Jul 3 1997

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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