Eudesmane-Type Sesquiterpenoid and Guaianolides from <i>Kandelia candel</i> in a Screening Program for Compounds to Overcome TRAIL Resistance

In a screening program for natural products that can overcome TRAIL resistance, a new eudesmane-type sesquiterpenoid (<b>1</b>), three new guaianolides, mehirugins A–C (<b>2</b>–<b>4</b>), and two known guaianolides (<b>5</b> and <b>6</b>) were isolated from a MeOH extract of <i>Kandelia candel</i> leaves. Compounds <b>1</b> and <b>3</b>–<b>6</b> in combination with TRAIL showed cytotoxic activity in sensitizing TRAIL-resistant human gastric adenocarcinoma cells

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

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

Xylogranin B: A Potent Wnt Signal Inhibitory Limonoid from <i>Xylocarpus granatum</i>

Xylogranin B (<b>2</b>) was isolated from <i>Xylocarpus granatum</i> (Meliaceae) leaves, by use of a cell-based luciferase screening system targeting a Wnt signaling pathway. Compound <b>2</b> inhibited TCF/β-catenin transcriptional activity (IC₅₀ 48.9 nM) and exhibited strong cytotoxicity against colon cancer cell lines. Compound <b>2</b> significantly decreased β-catenin protein levels in nuclei but not in the cytosol. These results indicated that a decrease in β-catenin levels in nuclei by <b>2</b> resulted in the Wnt signal inhibitory effects of <b>2</b>