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.

Salidroside, a Chemopreventive Glycoside, Diminishes Cytotoxic Effect of Cisplatin in Vitro

“… found SAL‐induced inhibition of mTOR pathway in bladder cancer cells while minimal effect on the growth of non‐malignant bladder cell line was observed. As shown in our experiments, CDDP can arrest both sensitive A2780 as well as resistant A2780/CP cells in G2/M phase of cell cycle what is in line with findings of several reports published on various human ovarian carcinoma cells . This CDDP‐induced G2/M phase arrest was accompanied by increased level of DNA damage manifested as the reduced migration of DNA into the tails of comets observed by us in the present investigation, by Hunakova et al .…”

Improving anticancer activity towards colon cancer cells with a new p53‐activating agent

“…Interestingly and in contrast to the experience with doxorubicin, colon cancer cells did not develop acquired-resistance to SYNAP, thus avoiding the drug resistance feature displayed by many chemotherapeutic agents in cancer cells. Also, although cancer cells resistant to one drug can exhibit cross-resistance to other drugs (Zanjirband et al, 2016;Lopez and Banerji, 2017), in our work, doxorubicin-resistant cells showed no cross-resistance to SYNAP. Indeed, SYNAP was able to resensitize doxorubicin-resistant colon cancer cells to the effect of doxorubicin, leading to a marked reduction in its effective dose.…”

Interaction with AEG-1 and MDM2 is associated with glioma development and progression and correlates with poor prognosis

“…As a critical negative regulator of p53 which is a key regulator of cell cycle checkpoints, MDM2 overexpression decreases p53 protein levels and function leading to accelerated tumor formation and progression [34]. Recent investigations have identified MDM2 is amplified in a variety of human tumours of diverse tissue origins including non-small cell lung cancer, ovarian carcinoma, prostate cancer, and glioblastoma [35][36][37][38]. MDM2 protein levels and activity are regulated by various oncogenic and tumor suppressive pathways [39].…”