Differential effects of resveratrol and novel resveratrol derivative, HS-1793, on endoplasmic reticulum stress-mediated apoptosis and Akt inactivation

Abstract

. Since resveratrol (3,4',5 tri-hydroxystilbene), which has been shown to inhibit multistage carcinogenesis, is not a potent cytotoxic compound, several studies were undertaken to obtain synthetic analogues of resveratrol with potent activity. We previously reported that a resveratrol derivative HS-1793 exhibits stronger antitumor effects than resveratrol in several cancer cell types. The present study was undertaken to reveal precise mechanism by which HS-1793 induces cell death. The induction of CCAAT/enhancerbinding protein-homologous protein (CHOP) and glucoseregulated protein (GRP)-78, and ER stress-specific XBP1 splicing were found in HT29 human colon carcinoma cells treated with resveratrol. Conversely, these manifestations were not observed in HT29 cells treated with HS-1793. Inhibition of caspase-4 activity by z-LEVD-fmk significantly reduced the induction of apoptosis by resveratrol but not by HS-1793. These findings suggest that HS-1793, contrary to resveratrol, does not induce ER stress-mediated apoptosis. Importantly, we observed that HS-1793 but not resveratrol decreased phosphorylated Akt level. We also demonstrated that HS-1793, compared to resveratrol, exerted more effective apoptosis inducing activity in Akt-activated cells. Taken together, the stronger antitumor activity of HS- 1793 originates, at least in part, from its ability for Akt inactivation.