title: The MDM2-inhibitor Nutlin-3 synergizes with cisplatin to induce p53 dependent tumor cell apoptosis in non-small cell lung cancer.
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.
authors.affiliation: Center for Oncological Research (CORE), University of Antwerp, Antwerp, Belgium.|Department of Pathology, Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Christophe
authors.initials: C
authors.lastname: Deben
authors.affiliation: Center for Oncological Research (CORE), University of Antwerp, Antwerp, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Wouters
authors.affiliation: Center for Oncological Research (CORE), University of Antwerp, Antwerp, Belgium.|Center for Medical Genetics, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
authors.forename: Ken
authors.initials: K
authors.lastname: Op de Beeck
authors.affiliation: Center for Oncological Research (CORE), University of Antwerp, Antwerp, Belgium.
authors.forename: Jolien
authors.initials: J
authors.lastname: van Den Bossche
authors.affiliation: Center for Oncological Research (CORE), University of Antwerp, Antwerp, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: Jacobs
authors.affiliation: Department of Pathology, Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Karen
authors.initials: K
authors.lastname: Zwaenepoel
authors.affiliation: Center for Oncological Research (CORE), University of Antwerp, Antwerp, Belgium.|Department of Medical Oncology, Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: Peeters
authors.affiliation: Department of Thoracic Oncology, Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Van Meerbeeck
authors.affiliation: Center for Oncological Research (CORE), University of Antwerp, Antwerp, Belgium.
authors.forename: Filip
authors.initials: F
authors.lastname: Lardon
authors.affiliation: Department of Medical Oncology, Antwerp University Hospital, Antwerp, Belgium.|Phase-1 Early Clinical Trials Unit, Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Christian
authors.initials: C
authors.lastname: Rolfo
authors.affiliation: Center for Oncological Research (CORE), University of Antwerp, Antwerp, Belgium.|Department of Pathology, Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Deschoolmeester
authors.affiliation: Center for Oncological Research (CORE), University of Antwerp, Antwerp, Belgium.|Department of Pathology, Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Pauwels
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology*; D004334:Drug Administration Schedule; D004357:Drug Synergism; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D007093:Imidazoles; D010879:Piperazines; D012333:RNA, Messenger; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D002945:Cisplatin
keywords: MDM2; NSCLC; cisplatin; p53; synergism