Piceatannol-Induced Apoptosis Is Reversed by N-Acetyl-L-cysteine through Restoration of XIAP Expression

Piceatannol, a naturally occurring stilbene derivative mainly found in grapes, possesses apoptotic activity in various cancer cell lines, in addition to potent antioxidant activity. In the current study, we showed that piceatannol exhibits potent cytotoxic effects in all tested leukemia cell lines (THP-1, HL-60, U937, and K562). These effects were accompanied by induction of DNA damage, an increase in the proportion of cells in the sub-G(1) phase of the cell cycle, and inhibition of reactive oxygen species (ROS) generation. However, N-acetyl-L-cysteine (NAC), a strong ROS scavenger, significantly inhibited piceatannol-induced apoptosis, suggesting that piceatannol-induced apoptosis does not occur via inhibition of ROS generation. Piceatannol also resulted in a significant increase in mitochondrial depolarization, along with a decline in Bcl-2 expression, which was not restored by NAC. Conversely, ectopic Bcl-2 overexpression moderately inhibited piceatannol-induced apoptosis. Furthermore, piceatannol strongly inhibited X-linked inhibitor of apoptosis protein (XIAP) expression, which was restored by NAC. A transient knockdown of XIAP significantly increased piceatannol-induced apoptosis in the presence of NAC, suggesting that XIAP downregulation increases piceatannol-induced apoptosis, and that NAC could reverse this effect by increasing XIAP expression. Taken together, these results suggest that piceatannol induces apoptosis in human leukemia cell lines by downregulating XIAP expression, regardless of antioxidant activity.