Abstract 4441: Stichoposides induce apoptosis through the generation of ceramide in human leukemia cells

Abstract

Abstract Marine triterpene glycosides are physiologically active natural compounds, isolated from sea cucumbers (holothurians) and demonstrate a wide spectrum of biological effects. Stichoposides are extracted from Thelenota anax (family Stichopodidae). Previous studies demonstrated that stichoposides had antifungal, cytotoxic, and antitumor activities. However, the specific molecular mechanisms underlying this effect remain to be elucidated. Stichoposide-induced apoptosis was examined in human leukemia cells in relation to mitochondrial injury and perturbations in signaling pathways. Stichoposide C (STC) induces apoptosis in these cells in a dose-dependent manner and leads to the activation of FAS, recruitment of FADD, activation of caspase-8, cleavage of Bid, mitochondrial damage and activation of caspase-3. In contrast, stichoposide D (STD) induces apoptosis in these cells in a dose-dependent manner and causes to activation of extrinsic pathway, not to activation of intrinsic pathway. In addition, STC- and STD-induced apoptosis are mediated by ER stress pathway, showing that Salubrinal, ER pathway inhibitor, inhibits apoptosis by STC and STD. STD activated acid sphingomyelinase (SMase) and neutral SMase, resulting in the generation of ceramide, but STC slightly activated them. By using specific inhibitor for acid SMase or neutral SMase and siRNA knockdown experiments, stichoposides-induced apoptosis was blocked. Thus, these results indicate that ceramide generation by stichoposides may contribute to stichoposides-induced apoptosis. Thus, these data suggest that stichoposides may have therapeutic relevance in the treatment of human leukemia. This study was supported by the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korea government (MEST) through the Medical Research Center for Cancer Molecular Therapy at Dong-A University (R13-2002-044-05002-0). 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 4441.