Selective Killing Of Cancer Cells With Mitochondrial Respiratory Dysfunction Induced By Activation Of Oncogenic Ras

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Mitochondrial dysfunction is an important mechanism by which cancer cells become resistant to chemotherapeutic agents. Oncogenic Ras activation is often observed in human cancer and was reported to cause mitochondrial dysfunction by compromising mitochondrial electron transport chain. Therefore, identification of new agents capable of effectively killing mitochondrial defective cancer cells would have important therapeutic implications. Our previous work has discovered that mitochondrial respiratory dysfunction could cause increased NADPH oxidase (NOX) activity to support cell survival in the metabolic switch from mitochondrial oxidative phosphorylation to glycolysis. Mitochondrial respiratory dysfunction can also cause profound redox alteration to adapt ROS stress. Here, we report that targeted inhibition of NOX and glutathione synthesis has synergy effect in killing mitochondrial respiratory dysfunction cells, including cancer cells harboring oncogenic Ras activation. Activation of NOX and increased glutathione antioxidants are always observed in Ras activated cells. Treatment of these cancer cells with DPI and BSO to inhibit NOX activity and antioxidant adaptation function resulted in an elevated ROS stress, increased gamma-H2AX expression, leading to massive death of the cancer cells, such as Panc-1 and HCT116 cells. Antioxidant NAC and catalase attenuated the BSO and DPI induced cell death in mitochondrial respiratory dysfunction cells. The synergistic effect of BSO and DPI to kill oncogenic Ras bearing HCT116 cells was further confirmed using colony formation assay. Our results suggest that DPI, in synergy with BSO, is a promising compound capable of killing cancer cells bearing oncogenic Ras mutations through a ROS-mediated mechanism and warrants further investigations. Citation Format: Weiqin Lu, Yaying Yang, Craig Logsdon, Peng Huang. Selective killing of cancer cells with mitochondrial respiratory dysfunction induced by activation of oncogenic Ras. [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 806. doi:10.1158/1538-7445.AM2014-806