Abstract 946: Mitochondrial division inhibitor 1 (mdivi-1) overcomes cisplatin resistance independent of dynamin-related protein 1 (Drp1).

Platinum based anticancer agents including cisplatin are among the most effective and widely used anticancer drugs. However, the inherent and acquired resistance to these drugs in tumors present significant challenges in cancer treatment and directly lead to treatment failure. We have identified a number of thioquinazolinone derivatives, including the mitochondrial division inhibitor-1 (mdivi-1), that are able to effectively overcome both the inherent and acquired resistance to cisplatin and induce rapid apoptosis in several tumor cell lines. However, the enhanced cellular sensitivity to cisplatin by mdivi-1 was also observed in Drp1 (a mitochondrial fission protein and the supposed target of mdivi-1) knockout MEF cells, indicating Drp1-independent roles of these compounds in overcoming platinum drug resistance. The combination of cisplatin and mdivi-1 induces a robust replication stress response and enhances both intrinsic and extrinsic apoptotic signaling when compared with cisplatin or mdivi-1 treatment alone. Though the combined effect of cisplatin and mdivi-1 is not dependent on mitochondrial fission protein Drp1, mitochondria do play a significant role in the rapid execution of apoptosis triggered by this combination. Highly uncoupled mitochondria, increased generation of reactive oxygen species (ROS) and the release of apoptotic factors were observed only in cells treated with the combination of cisplatin and mdivi-1 and not in cells treated with the compounds individually. Taken together, we have identified novel functions for a set of thioquinazolinone derivatives that are able to overcome platinum drug resistance through enhancing replication stress-mediated apoptotic response. Citation Format: Wei Qian, Vera Roginskaya, Sandra Strychor, Jan Beumer, Lee McDermott, Jingnan Wang, Bennett Van Houten. Mitochondrial division inhibitor 1 (mdivi-1) overcomes cisplatin resistance independent of dynamin-related protein 1 (Drp1). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 946. doi:10.1158/1538-7445.AM2013-946