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

Abstract
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.
AuthorsRolly G Fuentes, Kazufumi Toume, Midori A Arai, Samir K Sadhu, Firoj Ahmed, Masami Ishibashi
JournalJournal of natural products (J Nat Prod) Vol. 78 Issue 4 Pg. 864-72 (Apr 24 2015) ISSN: 1520-6025 [Electronic] United States
PMID25793965 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Abietanes
  • Benzothiazoles
  • Leupeptins
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Necrosis Factor-alpha
  • beta Catenin
  • scopadulciol
  • Toluene
  • pifithrin
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde
Topics
  • Abietanes (chemistry, isolation & purification, pharmacology)
  • Adenocarcinoma (drug therapy)
  • Apoptosis (drug effects)
  • Benzothiazoles (pharmacology)
  • Down-Regulation (drug effects)
  • Humans
  • Leupeptins (pharmacology)
  • Molecular Structure
  • Receptors, TNF-Related Apoptosis-Inducing Ligand (drug effects, genetics)
  • Scoparia (chemistry)
  • Stomach Neoplasms (drug therapy)
  • TNF-Related Apoptosis-Inducing Ligand (metabolism)
  • Toluene (analogs & derivatives, pharmacology)
  • Tumor Necrosis Factor-alpha (metabolism)
  • beta Catenin (metabolism)

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