Abstract 5658: Quercetin induces tumor-selective apoptosis involving downregulation of Mcl-1 and activation of Bax

Abstract Quercetin is a promising antitumor agent that induces apoptosis in a variety of tumor cells. However, the underlying mechanisms how this drug works are unclear. Here we report that administration of quercetin in human leukemia cells resulted in marked release of cytochrome c, cleavage of caspase 8, 9, 7 and 3, and apoptosis. Pronounced apoptosis was also noted in diverse primary leukemia cells but not in normal blood peripheral mononuclear cells. These events were accompanied by Mcl-1 down-regulation, most likely through a rapid dephosphorylation of translation initiation factor eIF4E. Following quercetin, Bax protein underwent conformational change and mitochondrial translocation which triggered cytochrome c release. Knockdown Bax by siRNA partially reversed querctin-induced apoptosis. Essentially, knockout of Bax completely abrogated the activation of caspase 9, 7 and 3, PARP cleavage and apoptosis, indicating that Bax is primarily required for quercetin lethality. Ectopic expression of Mcl-1 attenuated quercetin-mediated Bax activation, translocation and cell death. Conversely, interruption of Mcl-1 by siRNA enhanced Bax activation and translocation, as well as lethality induced by quercetin. However, the absence of Bax had no effect on quercetin-mediated Mcl-1 down-regulation. These results suggest that Mcl-1 may operate upstream of Bax. Finally, addition of quercetin increased Bid cleavage. The caspase 8 specific inhibitor prevented Bid cleavage, Bax activation, and subsequent caspase 3 processing. Knockout of Bax had no effect on the processing of caspase 8 and Bid. These observations indicate that Bax activation is also mediated by caspase 8 dependent Bid cleavage upon quercetin treatment. Collectively, these findings demonstrate that quercetin mediates Mcl-1 down-regulation and Bid cleavage which potentiate Bax activation and mitochondrial translocation, events that cooperate to engage the intrinsic and extrinsic apoptotic cascades, and apoptosis. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5658.