Scopadulciol (1), a scopadulan-type
diterpenoid, was isolated from Scoparia dulcis along with three other compounds (2-4) by an activity-guided approach using the TCF reporter (TOP)
luciferase-based assay system. A fluorometric microculture cytotoxicity assay (FMCA) revealed that compound 1 was cytotoxic to AGS human gastric
adenocarcinoma cells. The treatment of AGS cells with 1 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 1. The 1-induced degradation of β-
catenin was also abrogated in the presence of
pifithrin-α, an inhibitor of p53 transcriptional activity. Compound 1 inhibited TOP activity in AGS cells and downregulated the
protein levels of
cyclin D1, c-myc, and
survivin. Compound 1 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 1 induced the p53- and
proteasome-dependent degradation of β-
catenin, which resulted in the inhibition of TCF/β-
catenin transcription in AGS cells. Furthermore, 1 enhanced apoptosis in TRAIL-resistant AGS when combined with TRAIL.