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.
Vikhanskaya
F
F
Department of Experimental Oncology, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
Clerico
L
L
Valenti
M
M
Stanzione
M S
MS
Broggini
M
M
Parodi
S
S
Russo
P
P
D002945:Cisplatin / Q000494:pharmacology*; D053938:DNA Fragmentation; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D002945:Cisplatin