The MDM2-inhibitor Nutlin-3 synergizes with cisplatin to induce p53 dependent tumor cell apoptosis in non-small cell lung cancer

Abstract

// Christophe Deben 1,2 , An Wouters 1 , Ken Op de Beeck 1,4 , Jolien van Den Bossche 1 , Julie Jacobs 1 , Karen Zwaenepoel 2 , Marc Peeters 1,3 , Jan Van Meerbeeck 5 , Filip Lardon 1 , Christian Rolfo 3,6 , Vanessa Deschoolmeester 1,2,* and Patrick Pauwels 1,2 1 Center for Oncological Research (CORE), University of Antwerp, Antwerp, Belgium 2 Department of Pathology, Antwerp University Hospital, Antwerp, Belgium 3 Department of Medical Oncology, Antwerp University Hospital, Antwerp, Belgium 4 Center for Medical Genetics, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium 5 Department of Thoracic Oncology, Antwerp University Hospital, Antwerp, Belgium 6 Phase-1 Early Clinical Trials Unit, Antwerp University Hospital, Antwerp, Belgium * These author is a Co-senior author Correspondence to: Christian Rolfo, email: // Keywords : cisplatin, MDM2, p53, NSCLC, synergism Received : March 30, 2015 Accepted : May 30, 2015 Published : June 10, 2015 Abstract The p53/MDM2 interaction has been a well-studied target for new drug design leading to the development of the small molecule inhibitor Nutlin-3. Our objectives were to combine Nutlin-3 with cisplatin (CDDP), a well-known activator of the p53 pathway, in a series of non-small cell lung cancer cell lines in order to increase the cytotoxic response to CDDP. We report that sequential treatment (CDDP followed by Nutlin-3), but not simultaneous treatment, resulted in strong synergism. Combination treatment induced p53’s transcriptional activity, resulting in increased mRNA and protein levels of MDM2, p21, PUMA and BAX. In addition we report the induction of a strong p53 dependent apoptotic response and induction of G2/M cell cycle arrest. The strongest synergistic effect was observed at low doses of both CDDP and Nutlin-3, which could result in fewer (off-target) side effects while maintaining a strong cytotoxic effect. Our results indicate a promising preclinical potential, emphasizing the importance of the applied treatment scheme and the presence of wild type p53 for the combination of CDDP and Nutlin-3.