Abstract 2132: Deferoxamine and Deferasirox enhance anticancer effects of apoptosis in gastric cancer cells

Abstract

Abstract Deferoxamine(DFO) and Deferasirox(DFRA) is an iron chelating agent that has been used extensively to treat acute iron detoxification and chronically iron overloaded patients. Recent reports have been shown that iron chelators induce anti-proliferative effect in multiple leukemia cells. However, their roles and the underlying mechanism in anti-tumorigenic function of solid tumor, especially gastric cancer, are not yet known. In this work, we evaluated the anti-tumorigenic action of these two iron chelating agent with gastric cancer cell line, and investigated their apoptosis-inducing effects as the potential mechanism in this process. The results show that both of them induce the growth inhibitory effects in both dose- and time-dependent fashion in gastric cancer cell line AGS and SNU-638. Cell cycle analysis by FACS indicated that both DFO/DFRA-treated cell lines showed an increase in the proportion of cells in sub-G1 phase, compared to untreated cells. Exposure of gastric cancer cells to DFO/DFRA also resulted in the increase in the percentage of annexin V- positive and PI-negative cells. The results by multiple in vitro experimental model, showed that DFO /DFRA induce these gastric cancer cells to undergo apoptosis with a release of cytichrome C from mitochondria, the activation of caspase-3/9, the cleavage of PARP, the cleavage of anti-apoptotic protein Bcl-2, together with the accumulation of pro-apoptotic protein Bax and Bim. Furthermore, knock-down of Bax and Bim expression by RNA interference virtually eliminated DFO/DFRA-induced apoptosis. Importantly, inhibition of JNK kinase activity demonstrated that DFO/DFRA-induced apoptotic pathway was regulated by the JNK signaling cascade In conclusion, this finding indicates that iron-chelating agent, DFO and DFRA, promotes apoptosis of gastric cancer cells by sequential activation of the JNK signaling pathway followed by the up-regulation of intrinsic pathway of Bax/Bim-caspase 3/9. 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 2132. doi:10.1158/1538-7445.AM2011-2132