Ovarian cancer is the fifth leading cause of
cancer-related female deaths. Due to serious side effects, relapse and resistance to standard
chemotherapy, better and more targeted approaches are required. Mutation of the TP53 gene accounts for 50% of all human
cancers. In the remaining
malignancies, non-genotoxic activation of wild-type p53 by small molecule inhibition of the MDM2-p53 binding interaction is a promising therapeutic strategy. Proof of concept was established with the cis-
imidazoline Nutlin-3, leading to the development of
RG7388 and other compounds currently in early phase clinical trials. This preclinical study evaluated the effect of
Nutlin-3 and
RG7388 as single agents and in combination with
cisplatin in a panel of
ovarian cancer cell lines. Median-drug-effect analysis showed
Nutlin-3 or
RG7388 combination with
cisplatin was additive to, or synergistic in a p53-dependent manner, resulting in increased p53 activation, cell cycle arrest and apoptosis, associated with increased p21WAF1
protein and/or
caspase-3/7 activity compared to
cisplatin alone. Although MDM2 inhibition activated the expression of p53-dependent DNA repair genes, the growth inhibitory and pro-apoptotic effects of p53 dominated the response. These data indicate that combination treatment with MDM2 inhibitors and
cisplatin has synergistic potential for the treatment of
ovarian cancer, dependent on cell genotype.