Scopadulciol, Isolated from <i>Scoparia dulcis</i>, Induces β‑Catenin Degradation and Overcomes Tumor Necrosis Factor-Related Apoptosis Ligand Resistance in AGS Human Gastric Adenocarcinoma Cells

Abstract

Scopadulciol (<b>1</b>), a scopadulan-type diterpenoid, was isolated from <i>Scoparia dulcis</i> along with three other compounds (<b>2</b>–<b>4</b>) by an activity-guided approach using the TCF reporter (TOP) luciferase-based assay system. A fluorometric microculture cytotoxicity assay (FMCA) revealed that compound <b>1</b> was cytotoxic to AGS human gastric adenocarcinoma cells. The treatment of AGS cells with <b>1</b> decreased β-catenin levels and also inhibited its nuclear localization. The pretreatment of AGS cells with a proteasome inhibitor, either MG132 or epoxomicin, protected against the degradation of β-catenin induced by <b>1</b>. The <b>1</b>-induced degradation of β-catenin was also abrogated in the presence of pifithrin-α, an inhibitor of p53 transcriptional activity. Compound <b>1</b> inhibited TOP activity in AGS cells and downregulated the protein levels of cyclin D1, c-myc, and survivin. Compound <b>1</b> also sensitized AGS cells to tumor necrosis factor-related apoptosis ligand (TRAIL)-induced apoptosis by increasing the levels of the death receptors, DR4 and DR5, and decreasing the level of the antiapoptotic protein Bcl-2. Collectively, our results demonstrated that <b>1</b> induced the p53- and proteasome-dependent degradation of β-catenin, which resulted in the inhibition of TCF/β-catenin transcription in AGS cells. Furthermore, <b>1</b> enhanced apoptosis in TRAIL-resistant AGS when combined with TRAIL