title: A novel synthetic 1,3-phenyl bis-thiourea compound targets microtubule polymerization to cause cancer cell death.
abstract: Microtubules are essential cytoskeletal components with a central role in mitosis and have been particularly useful as a cancer chemotherapy target. We synthesized a small molecule derivative of a symmetrical 1,3-phenyl bis-thiourea, (1,1'-[1,3-phenylene]bis[3-(3,5-dimethylphenyl)thiourea], named "41J"), and identified a potent effect of the compound on cancer cell survival. 41J is cytotoxic to multiple cancer cell lines at nanomolar concentrations. Cell death occurred by apoptosis and was preceded by mitotic arrest in prometaphase. Prometaphase arrest induced by 41J treatment was accompanied by dissociation of cyclin B1 levels from the apparent mitotic stage and by major spindle abnormalities. Polymerization of purified tubulin in vitro was directly inhibited by 41J, suggesting that the compound works by directly interfering with microtubule function. Compound 41J arrested the growth of glioblastoma multiforme xenografts in nude mice at doses that were well-tolerated, demonstrating a relatively specific antitumor effect. Importantly, 41J overcame drug resistance due to β-tubulin mutation and P-glycoprotein overexpression. Compound 41J may serve as a useful new lead compound for anticancer therapy development.
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics; Mayo Clinic College of Medicine; Rochester, MN USA.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Shing
authors.affiliation: Department of Pharmacology; Case Western Reserve University School of Medicine; Cleveland, OH USA.
authors.forename: Jae Won
authors.initials: JW
authors.lastname: Choi
authors.affiliation: Department of Chemistry; University of Georgia; Athens, GA USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Chapman
authors.affiliation: Department of Radiation Oncology; Mayo Clinic College of Medicine; Rochester, MN USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Schroeder
authors.affiliation: Department of Radiation Oncology; Mayo Clinic College of Medicine; Rochester, MN USA.
authors.forename: Jann N
authors.initials: JN
authors.lastname: Sarkaria
authors.affiliation: Department of Chemistry; University of North Florida; Jacksonville, FL USA.
authors.forename: Abdul
authors.initials: A
authors.lastname: Fauq
authors.affiliation: Department of Pediatric and Adolescent Medicine; Mayo Clinic College of Medicine; Rochester, MN USA; Department of Immunology; Mayo Clinic College of Medicine; Rochester, MN USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Bram
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D016543:Central Nervous System Neoplasms / Q000188:drug therapy; D003412:Cricetulus; D056744:Cyclin B1 / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005909:Glioblastoma / Q000188:drug therapy; D064593:Heterografts; D006801:Humans; D008819:Mice, Nude; D008870:Microtubules / Q000378:metabolism*; D058105:Polymerization; D049468:Prometaphase / Q000187:drug effects; D008941:Spindle Apparatus / Q000187:drug effects; D013890:Thiourea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D014404:Tubulin / Q000378:metabolism
chemical_list: C000595180:1,1'-(1,3-phenylene)bis(3-(3,5-dimethylphenyl)thiourea); D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D056744:Cyclin B1; D014404:Tubulin; D013890:Thiourea
keywords: chemotherapy; drug resistance; microtubule; mitosis; xenograft
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