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

Hes1-Binding Compounds Isolated by Target Protein Oriented Natural Products Isolation (TPO-NAPI)

Hairy and enhancer of split 1 (Hes1) is a transcription factor that acts in neural stem cells to inhibit differentiation. We recently developed target protein oriented natural products isolation (TPO-NAPI) using Hes1-immobilized beads to identify activators of neural stem cells. Isomicromonolactam (<b>1</b>), staurosporin (<b>2</b>), and linarin (<b>3</b>) were isolated as Hes1-binding compounds using the TPO-NAPI method. Of these, compound <b>1</b> enhanced neural stem cell differentiation. Using truncated Hes1 proteins, the binding region of Hes1 for <b>1</b> was estimated to be in the C-terminal half that includes a TLE/Grg binding site. The differentiation-promoting activity of inohanamine (<b>4</b>) is also reported

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>

Boesenberols, Pimarane Diterpenes with TRAIL-Resistance-Overcoming Activity from <i>Boesenbergia pandurata</i>

TRAIL is a potent and selective inducer of apoptosis in most cancer cells while sparing normal cells, which makes it an attractive target for the development of new cancer therapies. In a screening program on natural resources with the ability to abrogate TRAIL resistance, the bioassay-guided fractionation of <i>Boesenbergia pandurata</i> rhizomes resulted in the isolation of 17 pimarane diterpenes and a monoterpene. Among these, compounds <b>1</b>–<b>8</b>, named boesenberols A–H, are new pimarane diterpenes. All compounds exhibited TRAIL-resistance-overcoming activity in TRAIL-resistant AGS cells. Subtoxic doses of the major compound <b>9</b> sensitized AGS cells to TRAIL-induced apoptosis by up-regulating apoptosis-inducing proteins, such as DR4, DR5, p53, Fas, CHOP, Bak, and cleaved caspases-3, -8, and -9, and down-regulating the levels of cell survival proteins, such as Bcl-2, c-FLIP, and GSK-3β, in TRAIL-resistant AGS cells. Furthermore, compound <b>9</b> did not decrease the viability of noncancerous (HEK293) cells at concentrations up to 30 μM

Notch Inhibitors from <i>Calotropis gigantea</i> That Induce Neuronal Differentiation of Neural Stem Cells

Neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease occur due to loss of the structure and function of neurons. For the potential treatment of neurodegenerative diseases, accelerators of neuronal differentiation of neural stem cells (NSCs) have been focused on and a cell-based assay system for measuring Notch signaling pathway activity was constructed. Using this assay system, eight compounds isolated from <i>Calotropis gigantea</i> were identified as inhibitors of the Notch signaling pathway. <i>Hes1</i> and <i>Hes5</i> are target genes of the Notch signaling pathway, and compound <b>1</b>, called uscharin, decreased the protein levels of Hes1 and Hes5 in assay cells and MEB5 cells (mouse NSCs). Furthermore, uscharin (<b>1</b>) enhanced the differentiation of MEB5 cells into neurons. The mechanism of uscharin (<b>1</b>) for the Notch signaling inhibitory activity would be acceleration of the degradation of the Notch intracellular domain (NICD) in the MEB5 cells