Abstract 1722: Multidrug resistant P-glycoprotein mediates through Src-EGFR cascade to attenuate DNA-PK-mediated DNA repair

Abstract

Abstract We have synthesized several novel bifunctional alkylating derivatives of 3a-aza-cyclopenta[a]inden (BO-1012, BO-1005, BO-1099, and BO-1101) and demonstrated that they were more cytotoxic to multidrug resistant (MDR) cells, such as KBvin10, KBtax50, and CEM/VBL, than their parental cells. Using xenograft model, we confirmed that BO-1012 was more effective to suppress the growth of MDR KBvin10 cells in nude mice than to the parental KB cells. To explore the possible mechanism, we revealed that KBvin10 and CEM/VBL MDR cells have significantly lower repair activity than KB and CEM parental cells. Our results also showed that reduced repair activity in KBvin10 cells was likely due to the defective in translocation of DNA-PK, a component of repair machinery of non-homologous end-joining, from cytosol into nucleus. Furthermore, we found that BO-1012 could activate Src kinase and trigger nuclear transport of EGFR in parental cells but not in MDR cells. Inhibition of Src resulted in suppression of BO-1012-induced EGFR translocation and consequently sensitized the parental cells to BO-1012. On the contrary, Src activation induced by BO-1012 was revived in MDR cells by using siRNA to reduce the expression of P-glycoprotein (P-gp). Meanwhile, P-gp silencing also facilitated the EGFR translocation and DNA repair in MDR cells treated with BO-1012. Taken together, our results demonstrated that overexpression of P-gp in MDR cells mediates through inhibition of Src-EGFR pathway to attenuate the DNA-PK-mediated repair. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1722. doi:10.1158/1538-7445.AM2011-1722