DDP-induced cytotoxicity is not influenced by p53 in nine human ovarian cancer cell lines with different p53 status.

Nine human ovarian cancer cell lines that express wild-type (wt) or mutated (mut) p53 were used to evaluate the cytotoxicity induced by cisplatin (DDP). The concentrations inhibiting the growth by 50% (IC50) were calculated for each cell line, and no differences were found between cells expressing wt p53 and mut p53. Using, for each cell line, the DDP IC50, we found that these concentrations were able to induce an increase in p53 levels in all four wt-p53-expressing cell lines and in one out of five mut-p53-expressing cell lines. WAF1 and GADD45 mRNAs were also increased by DDP treatment, independently of the presence of a wt p53. Bax levels were only marginally affected by DDP, and this was observed in both wt-p53- and mut-p53-expressing cells. DDP-induced apoptosis was evident 72 h after treatment, and the percentage of cells undergoing apoptosis was slightly higher for wt-p53-expressing cells. However, at doses near the IC50, the percentage of apoptotic cells was less than 20% in all the cell lines investigated. We conclude that the presence of wt p53 is not a determinant for the cytotoxicity induced by DDP in human ovarian cancer cell lines.

Sensitivity and cellular response to different anticancer agents of a human ovarian cancer cell line expressing wild-type, mutated or no p53.

BACKGROUND: The cytotoxicity and gene expression induced by anticancer drugs with different mechanisms of action was tested in clones from a human ovarian cancer cell line expressing no p53, mutated p53 or wild type (wt) p53. MATERIALS AND METHODS: We used clones from SKOV3 cells transfected with a temperature-sensitive mutant p53 which expresses mutated p53 at 37 degrees C and a wild type-like p53 at 32 degrees C. Cytotoxicity and expression of p53-related genes (WAF1 and GADD45) were tested after 24 hours of treatment with different drugs. RESULTS: All of the drugs were equally active in the different systems, independently of the presence of p53, with the exception of doxorubicin which was less cytotoxic in cells expressing a wtp53. An increase in the transcription of WAF1 and GADD45 genes was found in cells expressing p53 and treated with the drugs. GADD45 and WAF1 expression was also found in cells not expressing p53 but treated with the drugs, suggesting that these genes can also be activated by DNA damage through a pathway independent of p53. A highly DNA-sequence-specific alkylator, tallimustine (FCE 24517), which causes a very small number of DNA lesions, does not increase the expression of these genes. Cyclin D1 gene expression was not changed after treatment with the drugs tested in cells both expressing and not expressing wtp53. CONCLUSIONS: Our data suggest that p53 expression does not play a role in increasing the susceptibility of cells not undergoing apoptosis after DNA damage, but that, at least in the case of doxorubicin, it can enhance the repair systems and reduce the cytotoxicity.