title: 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.
authors: †Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.|⊥University of the Philippines Visayas Tacloban College, 6500 Tacloban City, Philippines.
authors: Rolly G
authors: RG
authors: Fuentes
authors: †Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
authors: Kazufumi
authors: K
authors: Toume
authors: †Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
authors: Midori A
authors: MA
authors: Arai
authors: ‡Pharmacy Discipline, Life Science School, Khulna University, Khulna 9208, Bangladesh.
authors: Samir K
authors: SK
authors: Sadhu
authors: §Department of Pharmaceutical Chemistry, University of Dhaka, Dhaka 1000, Bangladesh.
authors: Firoj
authors: F
authors: Ahmed
authors: †Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
authors: Masami
authors: M
authors: Ishibashi
mesh_terms: D045784:Abietanes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D000230:Adenocarcinoma / Q000188:drug therapy; D017209:Apoptosis / Q000187:drug effects; D052160:Benzothiazoles / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D015394:Molecular Structure; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000187:drug effects / Q000235:genetics; D036721:Scoparia / Q000737:chemistry*; D013274:Stomach Neoplasms / Q000188:drug therapy; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D045784:Abietanes; D052160:Benzothiazoles; D007976:Leupeptins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha; D051176:beta Catenin; C071755:scopadulciol; D014050:Toluene; C121565:pifithrin; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde