title: Sesquiterpenes with TRAIL-resistance overcoming activity from Xanthium strumarium.
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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan; Pharmacy Discipline, Life Science School, Khulna University, Khulna 9208, Bangladesh.
authors.forename: Utpal K
authors.initials: UK
authors.lastname: Karmakar
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Ishikawa
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Toume
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
authors.forename: Midori A
authors.initials: MA
authors.lastname: Arai
authors.affiliation: Pharmacy Discipline, Life Science School, Khulna University, Khulna 9208, Bangladesh.
authors.forename: Samir K
authors.initials: SK
authors.lastname: Sadhu
authors.affiliation: Department of Pharmaceutical Chemistry, University of Dhaka, Dhaka 1000, Bangladesh.
authors.forename: Firoj
authors.initials: F
authors.lastname: Ahmed
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan. Electronic address: mish@chiba-u.jp.
authors.forename: Masami
authors.initials: M
authors.lastname: Ishibashi
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D018515:Plant Leaves / Q000737:chemistry / Q000378:metabolism; D012717:Sesquiterpenes / Q000737:chemistry* / Q000302:isolation & purification / Q000633:toxicity; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D031210:Xanthium / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; D012717:Sesquiterpenes; D053221:TNF-Related Apoptosis-Inducing Ligand; D016159:Tumor Suppressor Protein p53; D020169:Caspases
keywords: Asteraceae; Sesquiterpenes; TRAIL-resistance; Xanthium strumarium