The effect of cisplatin and docetaxel on p53 and mdm2 in cancer cell lines

L Laatio MD a,b, R Serpi MSc a, U Puistola MD, PhD b, K Vahakangas MD, PhD a,c

a Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland, b Department of Obstetrics and Gynecology, University Hospital of Oulu, Oulu, Finland, c Department of Pharmacology and Toxicology, University of Kuopio, Kuopio, Finland

AIM: Malignant tumors often develop resistance towards chemotherapeutics, e.g. platinum compounds and taxanes, during cancer treatment. p53 tumor suppressor may be involved in the response of malignant tumors to cytostatics. We studied the effect of cisplatin and docetaxel on p53 and the main regulator of p53 degradation, mdm2, in two different cancer cell lines. METHODS: MCF-7 breast adenocarcinoma cells (wild type p53) and OVCAR-3 ovarian carcinoma cells (mutated p53) were treated with cisplatin and docetaxel. p53 and mdm2 proteins were studied by Western blotting using DO7 and H-221 antibodies, respectively. RESULTS: Compared to MCF-7, OVCAR-3 cells have notably higher basal expression of p53 due to a mutation in exon 7. Cisplatin treatment led to a strong induction of p53 in MCF-7, but not in OVCAR-3 cells. In MCF-7 cells the level of mdm2 was also increased by cisplatin while in OVCAR-3 cells it decreased. After docetaxel treatment the amount of both p53 and mdm2 increased in MCF-7 cells but decreased in OVCAR-3 cells. CONCLUSIONS: Cancer cell lines with different p53 status differ in their p53 and mdm2 responses to platinum and taxane compounds. Our results indicate that in MCF-7 cells mdm2 is not responsible for the induction of p53 by cisplatin and docetaxels. These results do not explain the reduction of p53 by docetaxel in OVCAR-3 cells and further studies are needed to clear this issue.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Novel Therapies, Part 1.