Novel Combination Approach Using Platinum Drugs And Mitochondrial Division Inhibitor 1 (Mdivi-1) Overcomes Platinum Resistance By Synergistically Inducing Mitochondrial Outer Membrane Permeabilization (Momp) And Apoptosis Independent Of Drp1

Platinum based anticancer agents, including cisplatin, are among the most effective and widely used anticancer drugs. However, inherent and acquired resistance to these drugs in tumors lead to treatment failure. We found a class of thioquinazolinone derivatives, including the mitochondrial division inhibitor-1 (mdivi-1), that overcome both the inherent and acquired resistance to cisplatin in tumor cell lines and also in primary ovarian tumors isolated from cisplatin refractory patients. The combination of cisplatin and mdivi-1 produces synergistic effect in inducing rapid apoptosis. Using Drp1 (a mitochondrial fission protein and the reported target of mdivi-1) knockout MEF cells we demonstrated that the combination of cisplatin and mdivi-1 overcomes cisplatin resistance in a Drp1-independent manner. Mdivi-1 causes replication defects and its combination with cisplatin triggers synergistic increases of replication stress and DNA damage. Comparing the treatment with cisplatin and mdivi-1 alone, the combination of the two agents enhances mitochondrial apoptotic signaling by specifically upregulating the expression of a pro-apoptotic Bcl-2 family protein Noxa, which promotes Bax/Bak-mediated mitochondrial outer membrane permeabilization (MOMP). Intriguingly, the combination of cisplatin and mdivi-1 also causes mitochondrial swelling that triggers a Bax/Bak-independent MOMP. Thus, the combination of cisplatin and mdivi-1 activates two distinct mechanisms that converge on mitochondria contributing to the enhancement of MOMP. This novel combination represents a potential effective strategy in overcoming platinum drug resistance by combining cisplatin with compounds that together are able to trigger the coinitiation of Bax/Bak-dependent and-independent mitochondrial apoptotic signaling. (Work was supported by P30CA047904, UPCI and PA Dept of Health CURE program) Citation Format: Wei Qian, Jingnan Wang, Vera Roginskaya, Lee McDermott, Robert Edwards, Donna Stolz, Fabien Llambi, Douglas Green, Bennett Van Houten. Novel combination approach using platinum drugs and mitochondrial division inhibitor 1 (mdivi-1) overcomes platinum resistance by synergistically inducing mitochondrial outer membrane permeabilization (MOMP) and apoptosis independent of Drp1. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1683. doi:10.1158/1538-7445.AM2014-1683