Novel combination of mitochondrial division inhibitor 1 (mdivi-1) and platinum agents produces synergistic pro-apoptotic effect in drug resistant tumor cells.

// Wei Qian 1 , Jingnan Wang 2 , Vera Roginskaya 1 , Lee A. McDermott 3 , Robert P. Edwards 4 , Donna B. Stolz 5 , Fabien Llambi 6 , Douglas R. Green 6 , Bennett Van Houten 1 1 Department of Pharmacology & Chemical Biology, School of Medicine, University of Pittsburgh and Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA 2 Tsinghua University School of Medicine, Tsinghua University, Haidian District, Beijing 100084, China 3 Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh and University of Pittsburgh Drug Discovery Institute, Pittsburgh, PA 15213, USA 4 Department of Obstetrics & Gynecology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA 5 Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA 6 Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA Correspondence: Wei Qian, email: // Bennett Van Houten, email: // Keywords : Platinum resistance, mdivi-1, replication stress, Noxa, mitochondrial swelling Received : March 18, 2014 Accepted : May 3, 2014 Published : May 4, 2014 Abstract Overcoming platinum drug resistance represents a major clinical challenge in cancer treatment. We discovered a novel drug combination using cisplatin and a class of thioquinazolinone derivatives including mdivi-1 (mitochondrial division inhibitor-1), that induces synergistic apoptosis in platinum resistant tumor cells, including those from cisplatin-refractory endstage ovarian cancer patients. However, through study of the combination effect on Drp1 (the reported target of mdivi-1) knockout MEF cells and the functional analysis of mdivi-1 analogs, we revealed that the synergism between mdivi-1 and cisplatin is Drp1-independent. Mdivi-1 impairs DNA replication and its combination with cisplatin induces a synergistic increase of replication stress and DNA damage, causing a preferential upregulation of a BH3-only protein Noxa. Mdivi-1 also represses mitochondrial respiration independent of Drp1, and the combination of mdivi-1 and cisplatin triggers substantial mitochondrial uncoupling and swelling. Upregulation of Noxa and simultaneous mitochondrial swelling causes synergistic induction of mitochondrial outer membrane permeabilization (MOMP), proceeding robust mitochondrial apoptotic signaling independent of Bax/Bak. Thus, the novel mode of MOMP induction by the combination through the “dual-targeting” potential of mdivi-1 on DNA replication and mitochondrial respiration suggests a novel class of compounds for platinum-based combination option in the treatment of platinum as well as multidrug resistant tumors.