Abstract 2959: Celarstrol enhances TNF-induced neuroblastoma cells death by promoting ROS-mediated programmed necrosis.

Abstract

Abstract Celastrol is an active ingredient of the traditional Chinese medicinal plant Tripterygium Wilfordii, which exhibits significant antitumor activity in different cancer models in vitro and in vivo. Previous studies have showed that celastrol kills cancer cells by inducing apoptosis, in this study, we reported that celastrol has potential to enhance TNF-induced necroptosis in SH-SY5Y neuroblastoma cells. Low dose of TNFα plus celastrol induced remarkable cell death which could be prevented by RIP1 kinase inhibitor Necrostatin-1, but exacerbated by caspase inhibitor Z-VAD-FMK. The mechanism for celastrol to enhance TNF-induced necroptosis involves promoting prolonged JNK activation and inducing ROS accumulation. TNFα plus celastrol induced cell death and mitochondrial outer membrane permeabilization (MOMP) could be reversed by ROS scavenger BHA. In addition, Mdivi-1, an inhibitor of mitochondrial fission protein Drp-1, could also block TNFα plus celastrol induced cell death and MOMP, which is consistent with previous elucidation that RIP1/RIP3 mediated cell death signal through Drp-1 to induced necroptosis. The effect of celastrol on enhancing cancer cells programmed necrosis may provide a new way to overcome the resistance chemotherapy induced by evading apoptosis in some cancer cells. Citation Format: Ming Zhao, Song Lin, Xiang Cheng, Guozhu Chen, Xiaodan Yu. Celarstrol enhances TNF-induced neuroblastoma cells death by promoting ROS-mediated programmed necrosis. [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 2959. doi:10.1158/1538-7445.AM2013-2959 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.