title: From fighting depression to conquering tumors: a novel tricyclic thiazepine compound as a tubulin polymerization inhibitor.
abstract: A novel tricyclic thiazepine derivative, 6-(p-tolyl)benzo[f] pyrido[2,3-b][1,4] thiazepine 11,11-dioxide (TBPT), exhibits potent inhibitory effects in two non-small-cell lung cancer cell lines, H460 and its drug-resistant variant, H460(TaxR), while exhibiting much less toxic effects on normal human fibroblasts. After five injections of TBPT at a dose of 60 mg/kg, it inhibits H460(TaxR) tumor growth in xenografted mouse models by 66.7% without causing observable toxicity to normal tissues. Based on gene perturbation data and a series of investigations, we reveal that TBPT is not a P-glycoprotein substrate and it inhibits microtubule formation by targeting tubulin, thereby causing cell cycle arrest at the G2/M stage and eventually inducing apoptosis. This redeployment of anti-depressant compound scaffold for anticancer applications provides a promising future for conquering drug-resistant tumors with fewer side effects.
authors.affiliation: School of Chemistry and Chemical Engineering, Shandong University, Jinan, Shandong, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Mu
authors.affiliation: School of Chemistry and Chemical Engineering, Shandong University, Jinan, Shandong, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: The Center for Combinatorial Chemistry and Drug Discovery of Jilin University, The School of Pharmaceutical Sciences and The College of Chemistry, Jilin University, Changchun, Jilin, China.
authors.forename: J
authors.initials: J
authors.lastname: Xiang
authors.affiliation: School of Chemistry and Chemical Engineering, Shandong University, Jinan, Shandong, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: School of Chemistry and Chemical Engineering, Shandong University, Jinan, Shandong, China.
authors.forename: S
authors.initials: S
authors.lastname: Zhai
authors.affiliation: The Rutgers Center for Computational and Integrative Biology, Camden, NJ, USA.
authors.forename: D P
authors.initials: DP
authors.lastname: Russo
authors.affiliation: The Rutgers Center for Computational and Integrative Biology, Camden, NJ, USA.|Department of Chemistry, Rutgers University, Camden, NJ, USA.
authors.forename: H
authors.initials: H
authors.lastname: Zhu
authors.affiliation: The Center for Combinatorial Chemistry and Drug Discovery of Jilin University, The School of Pharmaceutical Sciences and The College of Chemistry, Jilin University, Changchun, Jilin, China.
authors.forename: X
authors.initials: X
authors.lastname: Bai
authors.affiliation: School of Chemistry and Chemical Engineering, Shandong University, Jinan, Shandong, China.
authors.forename: B
authors.initials: B
authors.lastname: Yan
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D013841:Thiazepines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D013841:Thiazepines