title: Mdm2 inhibitors synergize with topoisomerase II inhibitors to induce p53-independent pancreatic cancer cell death.
abstract: Pancreatic ductal adenocarcinoma (PDAC) represents the fourth leading cause of cancer death in the western world, with a 5-year survival rate below 5%. Murine double minute 2 (Mdm2) is an important negative regulator of the tumor suppressor p53. Reactivation of wild-type p53 is a promising treatment strategy, and inhibitors of Mdm2 have already entered clinical trials. To investigate the effects of Mdm2 inhibitors in PDAC, we used a murine cell line platform with a genetically defined status of p53. Here, we describe that Mdm2 inhibitors can act on a subset of murine PDAC cell lines p53 independently. Furthermore, we observed that Mdm2 inhibitors increase the sensitivity of murine PDAC cell lines toward topoisomerase II inhibitors by inducing effector caspase-independent cell death. The combination of Mdm2 inhibitors with topoisomerase II inhibitors acts independent of the survival factor NFκB/RelA. Mechanistically, Mdm2 inhibitors increase topoisomerase II inhibitor-induced DNA double-strand breaks. We show that Mdm2 binds to Nbs1 of the Mre11-Rad50-Nijmegen breakage syndrome (Nbs) 1 DNA repair complex. In addition, we provide evidence that Mdm2 inhibitors delay DNA repair. These findings may help to design novel therapeutic strategies to overcome therapeutic resistance of PDAC.
authors.affiliation: II. Medizinische Klinik, Technische Universität München, München, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Conradt
authors.forename: Annika
authors.initials: A
authors.lastname: Henrich
authors.forename: Matthias
authors.initials: M
authors.lastname: Wirth
authors.forename: Maximilian
authors.initials: M
authors.lastname: Reichert
authors.forename: Marina
authors.initials: M
authors.lastname: Lesina
authors.forename: Hana
authors.initials: H
authors.lastname: Algül
authors.forename: Roland M
authors.initials: RM
authors.lastname: Schmid
authors.forename: Oliver H
authors.initials: OH
authors.lastname: Krämer
authors.forename: Dieter
authors.initials: D
authors.lastname: Saur
authors.forename: Günter
authors.initials: G
authors.lastname: Schneider
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D005047:Etoposide / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D011760:Pyrrolidinones / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology*; D000093542:Gemcitabine
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D000970:Antineoplastic Agents; D007093:Imidazoles; D007211:Indoles; C580662:PXN822; D010879:Piperazines; D011760:Pyrrolidinones; D059005:Topoisomerase II Inhibitors; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D003841:Deoxycytidine; C482205:nutlin 3; D005047:Etoposide; D004317:Doxorubicin; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D000093542:Gemcitabine