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

  • J Nat Prod. 2015 Apr 24;78(4):864-72. doi: 10.1021/np500933v.
Rolly G Fuentes  1  2 ,  Kazufumi Toume  1 ,  Midori A Arai  1 ,  Samir K Sadhu  3 ,  Firoj Ahmed  4 ,  Masami Ishibashi  1
Affiliations
  • 1. †Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
  • 2. ⊥University of the Philippines Visayas Tacloban College, 6500 Tacloban City, Philippines.
  • 3. ‡Pharmacy Discipline, Life Science School, Khulna University, Khulna 9208, Bangladesh.
  • 4. §Department of Pharmaceutical Chemistry, University of Dhaka, Dhaka 1000, Bangladesh.
PMID: 25793965 DOI: 10.1021/np500933v
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.

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