Inhibition of MDM2 via Nutlin-3A: A Potential Therapeutic Approach for Pleural Mesotheliomas with MDM2-Induced Inactivation of Wild-Type P53.

Robert F H Walter,Elena Mairinger,Clemens Aigner,Jeremias Wohlschlaeger,Agnes Bankfalvi,Thomas Mairinger,Jens Kollmeier,Jan Schmeller,Wilfried E E Eberhardt,Daniel C Christoph,Sabrina Borchert,Kurt W Schmid,Fabian D Mairinger,Thomas Hager,Michael Wessolly,Robert Werner,Till Plönes

doi:10.1155/2018/1986982

Abstract

Previously, our group demonstrated that nuclear expression of E3 ubiquitin ligase (MDM2) in malignant pleural mesothelioma (MPM) is significantly associated with decreased overall survival. A possible explanation may be that overexpression of MDM2 leads to a proteasomal degradation of TP53 that eventually results in a loss of TP53-induced apoptosis and senescence. It is well known from other tumor entities that restoration of TP53 activity, e.g., by MDM2 inhibition, results in an instant TP53-induced stress and/or DNA damage response of cancer cells. Nutlin-3A (a cis-imidazoline analogue) has been described as a potent and selective MDM2 inhibitor preventing MDM2-TP53-interaction by specific binding to the hydrophobic TP53-binding pocket of MDM2. In the present study, the effects of MDM2 inhibition in MPM via Nutlin-3A and standard platinum based chemotherapeutic agents were comparatively tested in three MPM cell lines (NCI-H2052, MSTO-211H, and NCI-H2452) showing different expression profiles of TP53, MDM2, and its physiological inhibitor of MDM2—P14/ARF. Our in vitro experiments on MPM cell lines revealed that Nutlin-3A in combination with cisplatin resulted in up to 9.75 times higher induction of senescence (p=0.0050) and up to 5 times higher apoptosis rate (p=0.0067) compared to the commonly applied cisplatin and pemetrexed regimens. Thus Nutlin-3A, a potent inhibitor of MDM2, is associated with a significant induction of senescence and apoptosis in MPM cell lines, making Nutlin-3A a promising substance for a targeted therapy in the subgroup of MPM showing MDM2 overexpression.

Highlights

Malignant mesothelioma is a highly aggressive tumor arising from mesothelial lined surfaces, mostly from the pleural cavities [1, 2]
Nutlin-3A induced senescence efficiently in all three malignant pleural mesothelioma (MPM) cell lines and was superior compared to cisplatin and/or pemetrexed, whereas apoptosis could only be induced at high concentrations
It is noteworthy that efficient delivery systems were developed using polymers as poly(lactide-coglycolide) (PLGA) and monoclonal antibodies [69]. In this in vitro study, our hypothesis that MDM2-overexpressing MPM can be targeted by a Nutlin-3A based chemotherapy was proven

Summary

Introduction

Malignant mesothelioma is a highly aggressive tumor arising from mesothelial lined surfaces, mostly from the pleural cavities (malignant pleural mesothelioma, MPM) [1, 2]. The median survival of patients is nine months [3,4,5]. MPM patients are negatively affected by mostly insufficient current treatment modalities consisting of platinumcontaining regimes using cisplatin [6] or carboplatin [7,8,9,10]. Testing Nutlin concentrations in comparison to Pemetrexed and Cisplatin 10nM Cisplatin 200nM Pemetrexed 10nm Cisplatin + 200nM Pemetrexed 5nM Nutlin 10nM Nutlin 20nM Nutlin. Testing Nutlin in combination with Cisplatin in comparison to Pemetrexed and Cisplatin 10nM Cisplatin 200nM Pemetrexed. Cisplatin treatment results in a response rate of merely 14% and a median survival of less than seven months [11]. The antifolate pemetrexed, as the only FDA-approved therapeutic for MPM, is used in combination with platin compounds [6,7,8,9,10]

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