title: Pre-clinical efficacy and synergistic potential of the MDM2-p53 antagonists, Nutlin-3 and RG7388, as single agents and in combined treatment with cisplatin in ovarian cancer.
abstract: 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.
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom.
authors.forename: Maryam
authors.initials: M
authors.lastname: Zanjirband
authors.affiliation: Faculty Institute for Cancer Sciences, University of Manchester, Manchester M13 9WL, United Kingdom.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Edmondson
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Lunec
mesh_terms: D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002470:Cell Survival; D002945:Cisplatin / Q000494:pharmacology*; D004260:DNA Repair; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D011759:Pyrrolidines / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*; D062366:para-Aminobenzoates / Q000494:pharmacology*
chemical_list: D007093:Imidazoles; D010879:Piperazines; D011759:Pyrrolidines; C586849:RG7388; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D062366:para-Aminobenzoates; C482205:nutlin 3; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D002945:Cisplatin
keywords: MDM2-p53 antagonists; Nutlin-3/RG7388; combined treatment; ovarian cancer; p53