RRC ID 67529
Author Karmakar UK, Ishikawa N, Toume K, Arai MA, Sadhu SK, Ahmed F, Ishibashi M.
Title Sesquiterpenes with TRAIL-resistance overcoming activity from Xanthium strumarium.
Journal Bioorg Med Chem
Abstract The ability of TRAIL to selectively induce apoptosis in cancer cells while sparing normal cells makes it an attractive target for the development of new cancer therapy. In search of bioactive natural products for overcoming TRAIL-resistance from natural resources, we previously reported a number of active compounds. In our screening program on natural resources targeting overcoming TRAIL-resistance, activity-guided fractionations of the extract of Xanthium strumarium led to the isolation of five sesquiterpene compounds (1-5). 11α,13-dihydroxanthinin (2) and 11α,13-dihydroxanthuminol (3) were first isolated from natural resources and xanthinosin (1), desacetylxanthanol (4), and lasidiol p-methoxybenzoate (5) were known compounds. All compounds (1-5) showed potent TRAIL-resistance overcoming activity at 8, 20, 20, 16, and 16 μM, respectively, in TRAIL-resistant AGS cells. Compounds 1 and 5 enhanced the levels of apoptosis inducing proteins DR4, DR5, p53, CHOP, Bax, cleaved caspase-3, cleaved caspase-8, and cleaved caspase-9 and also decreased the levels of cell survival protein Bcl-2 in TRAIL-resistant AGS cells in a dose-dependent manner. Compound 1 also enhanced the levels of DR4 and DR5 proteins in a time-dependent manner. Thus, compounds 1 and 5 were found to induce both extrinsic and intrinsic apoptotic cell death. Compound 1 also exhibit TRAIL-resistance overcoming activity in DLD1, DU145, HeLa, and MCF7 cells but did not decrease viability in non-cancer HEK293 cells up to 8 μM.
Volume 23(15)
Pages 4746-4754
Published 2015-8-1
DOI 10.1016/j.bmc.2015.05.044
PII S0968-0896(15)00454-X
PMID 26081757
MeSH Antineoplastic Agents, Phytogenic / chemistry* Antineoplastic Agents, Phytogenic / isolation & purification Antineoplastic Agents, Phytogenic / pharmacology Apoptosis Regulatory Proteins / metabolism Caspases / metabolism Cell Line, Tumor Cell Survival / drug effects Drug Resistance, Neoplasm / drug effects Drug Screening Assays, Antitumor HEK293 Cells HeLa Cells Humans MCF-7 Cells Magnetic Resonance Spectroscopy Molecular Conformation Plant Leaves / chemistry Plant Leaves / metabolism Sesquiterpenes / chemistry* Sesquiterpenes / isolation & purification Sesquiterpenes / toxicity TNF-Related Apoptosis-Inducing Ligand / pharmacology* Tumor Suppressor Protein p53 / metabolism Xanthium / chemistry* Xanthium / metabolism
IF 3.073
Human and Animal Cells MCF7(RCB1904)