Sanguinarine-induced apoptosis: Generation of ROS, down-regulation of Bcl-2, c-FLIP, and synergy with TRAIL

Sanguinarine is a benzophenanthridine alkaloid derived from the root of Sanguinaria canadensis and other poppy‐fumaria species, possessing potent antibacterial, antifungal, and anti‐inflammatory activities. In this study, we investigated the underling mechanisms by which sanguinarine induce apoptosis in human breast cancer MDA‐231 cells. Treatment of MDA‐231 cells with sanguinarine induced remarkable apoptosis accompanying the generation of ROS. Consistently, sanguinarine‐induced apoptosis was mediated by the increased reproductive cell death. Pretreatment with NAC or GSH attenuated sanguinarine‐induced apoptosis, suggesting the involvement of ROS in this cell death. During sanguinarin‐induced apoptosis, protein levels of pro‐caspase‐3, Bcl‐2, cIAP2, XIAP, and c‐FLIPs were reduced. Sanguinarine‐mediated apoptosis was substantially blocked by ectopic expression of Bcl‐2 and cFLIPs. Additionally, we found that sub‐lethal doses of sanguinarine remarkably sensitized breast cancer cells to TRAIL‐mediated apoptosis, but the cell death induced by sanguinarine and TRAIL in combination was not blocked by overexpression of Bcl‐2 or Akt. Therefore, combinatory treatment of sanguinarine and TRAIL may overcome the resistance of breast cancer cells due to overexpression of Akt or Bcl‐2. J. Cell. Biochem. 104: 895–907, 2008. © 2008 Wiley‐Liss, Inc.