6-Shogaol, a potent bioactive compound in ginger (Zingiber officinale Roscoe), 
has been reported for anti-inflammatory and anti-cancer activity. In this study, 
we investigated the effect of 6-shogaol to enhance tumor necrosis factor-related 
apoptosis-inducing ligand (TRAIL)-mediated apoptosis. The combined treatment 
with 6-shogaol and TRAIL markedly induces apoptosis in various cancer cells 
(renal carcinoma Caki cells, breast carcinoma MDA-MB-231 cells and glioma U118MG 
cells), but not in normal mesangial cells and normal mouse kidney cells. 
6-Shogaol reduced the mitochondrial membrane potential (MMP) and released 
cytochrome c from mitochondria to cytosol via Bax activation. Furthermore, we 
found that 6-shogaol induced down-regulation of c-FLIP(L) expression at the 
post-translational levels and the overexpression of c-FLIP(L) markedly inhibited 
6-shogaol plus TRAIL-induced apoptosis. Moreover, 6-shogaol increased reactive 
oxygen species (ROS) production in Caki cells. Pretreatment with ROS scavengers 
attenuated 6-shogaol plus TRAIL-induced apoptosis through inhibition of MMP 
reduction and down-regulation of c-FLIP(L) expression. In addition, 6-gingerol, 
another phenolic alkanone isolated from ginger, did not enhance TRAIL-induced 
apoptosis and down-regulate c-FLIP(L) expression. Taken together, our results 
demonstrated that 6-shogaol enhances TRAIL-mediated apoptosis in renal carcinoma 
Caki cells via ROS-mediated cytochrome c release and down-regulation of 
c-FLIP(L) expression.