TY - JOUR T1 - Sanguinarine Sensitizes Human Gastric Adenocarcinoma AGS Cells to TRAIL-mediated Apoptosis <em>via</em> Down-regulation of AKT and Activation of Caspase-3 JF - Anticancer Research JO - Anticancer Res SP - 4457 LP - 4465 VL - 29 IS - 11 AU - WOO YOUNG CHOI AU - CHENG-YUN JIN AU - MIN HO HAN AU - GI-YOUNG KIM AU - NAM DEUK KIM AU - WON HO LEE AU - SE-KWON KIM AU - YUNG HYUN CHOI Y1 - 2009/11/01 UR - http://ar.iiarjournals.org/content/29/11/4457.abstract N2 - Sanguinarine is a benzophenanthridine alkaloid, derived from the root of Sanguinaria canadensis and other poppy Fumaria species, which is known to have antimicrobial, antiinflammatory and antioxidant properties. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is known to induce apoptosis in cancer cells but spare most normal cells. However, its effects are limited in some types of cancer cells, including AGS human gastric adenocarcinoma cells. In the present study, we showed that treatment with TRAIL in combination with subtoxic concentrations of sanguinarine sensitized TRAIL-mediated apoptosis in AGS cells. Combined treatment with sanguinarine and TRAIL effectively induced Bid cleavage and loss of mitochondrial membrane potential, leading to the activation of caspases, and cleavage of poly(ADP-ribose) polymerase and β-catenin. The cytotoxic effects of the combined treatment were significantly inhibited by z-DEVD-fmk, a caspase-3 inhibitor, which demonstrates the important role of caspase-3 in the observed cytotoxic effect. In addition, the levels of Akt protein were markedly reduced in cells co-treated with sanguinarine and TRAIL. Apoptosis induced by the combined treatment was markedly increased by the phosphatidylinositol-3′-kinase inhibitor, LY294002 (Akt-upstream inhibitor), through the mitochondrial amplification step and caspase activation, suggesting that interactions of the synergistic effect were at least partially mediated through the Akt-dependent pathway. ER -