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

Maryam Zanjirband,John Lunec,Richard J Edmondson

doi:10.18632/oncotarget.9499

Maryam Zanjirband, John Lunec + Show 1 more

Open Access

https://doi.org/10.18632/oncotarget.9499

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Journal: Oncotarget	Publication Date: May 20, 2016
Citations: 53	License type: cc-by

Affiliation: Newcastle University, University of Manchester

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.

Highlights

Ovarian cancer is the most lethal of all gynecological malignancies and was reported to be responsible for approximately 152,000 deaths worldwide in 2012 [1]
The required concentration of each compound leading to 50% growth inhibition (GI50) showed that wild-type TP53 ovarian cancer cell lines were significantly more sensitive to Nutlin-3/RG7388 compared to mutant, which is consistent with their mechanism of action (p
The GI50 values for wild-type TP53 cell lines for RG7388 and Nutlin-3 were in the nanomolar range ( 253.3 ± 73.1 (SEM) nM) and micromolar range (1.76 ± 0.51 (SEM) μM) respectively

Summary

Introduction

Ovarian cancer is the most lethal of all gynecological malignancies and was reported to be responsible for approximately 152,000 deaths worldwide in 2012 [1]. Patients with primary disease respond to platinum and taxane chemotherapy, relapse and resistance to treatment is prevalent, leading to lack of long-term benefit from treatment. For this reason, molecular alterations in tumors, those involved in growth signaling pathways, cell cycle progression and apoptosis are being investigated to potentially exploit for targeted therapy (reviewed by [2, 3]). The TP53 tumor suppressor gene is referred to as the most frequently altered gene in human cancers. P53 function is held in check through other mechanisms and reactivation of p53 is a potential therapeutic strategy (reviewed by [5])

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