P2.18 Augmentation of Trail-Induced Apoptosis by Tubeimoside-1 in Human Gastric Cancer Cells Via Inhibition Of The Nf-ΚB and Pi3K/Akt Signaling Pathways

Abstract

ABSTRACT Traditional medicines not only provide important notion for finding novel drugs, also may supportive to reallocate drug discovery paradigm from ‘finding new-entity drugs’ to ‘combining existing agents and may even the combinations between such agents. Previously, we found that Tubeimoside-1 (TBMS-1), a triterpenoid saponin from traditional Chinese medicine, significantly induces apoptosis in gastric cancer cells. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis and kills cancer cells with little or no adverse effects on normal cells. However, gastric cancer cells are less sensitive than other cancer cells to TRAIL-induced apoptosis. In the present study, we found that Tubeimoside-1 enhanced TRAIL-induced apoptosis in human gastric adenocarcinoma SGC-7901 cells. As indicated by assays that measure mitochondrial membrane integrity, pro-survival proteins, and activation of caspase-8, caspase-9, and caspase-3, TBMS-1 potentiated the TRAIL-induced apoptosis in human gastric cancer cells, and converted TRAIL-resistant cells to TRAIL-sensitive cells. Here, we demonstrate the first evidence that TBMS-1 effectively enhances TRAIL-mediated cytotoxicity by suppressing pro-survival proteins including survivin and XIAP. Upon treatment with TBMS-1, the levels of survival proteins were strongly suppressed in SGC-7901 cells. The down-regulation of these survival proteins could be regulated by repressing activation of NF-κB and Akt. TBMS-1 also inhibited TRAIL-induced transcriptional activity of NF-κB. In addition, this substance significantly enhanced both extrinsic and intrinsic apoptosis, which were induced by TRAIL. Taken together, the results of the present study suggest that TBMS-1 exhibits an ability to overcome TRAIL resistance and combination treatment of TRAIL together with TBMS-1 may be an effective regimen for the treatment of advanced gastric cancer.