title: A novel microtubule inhibitor, MT3-037, causes cancer cell apoptosis by inducing mitotic arrest and interfering with microtubule dynamics.
abstract: We investigated the anticancer potential of a new synthetic compound, 7-(3-fluorophenyl)-4-methylpyrido-[2,3-d]pyrimidin-5(8H)-one (MT3-037). We found that MT3-037 effectively decreased the cancer cell viability by inducing apoptosis. MT3-037 treatments led to cell cycle arrest at M phase, with a marked increase in both expression of cyclin B1 and cyclin-dependent kinase 1 (CDK1) as well as in CDK1 kinase activity. Key proteins that regulate mitotic spindle dynamics, including survivin, Aurora A/B kinases, and polo-like kinase 1 (PLK1), were activated in MT3-037-treated cells. MT3-037-induced apoptosis was accompanied by activation of a pro-apoptotic factor, FADD, and the inactivation of apoptosis inhibitors, Bcl-2 and Bcl-xL, resulting in the cleavage/activation of caspases. The activation of c-Jun N-terminal kinase (JNK) was associated with MT3-037-induced CDK1 and Aurora A/B activation and apoptosis. Immunofluorescence staining of tubulin indicated that MT3-037 altered tubulin networks in cancer cells. Moreover, an in vitro tubulin polymerization assay revealed that MT3-037 inhibited the tubulin polymerization by direct binding to tubulin. Molecular docking studies and binding site completion assays revealed that MT3-037 binds to the colchicine-binding site. Furthermore, MT3-037 significantly inhibited the tumor growth in both MDAMB-468 and Erlotinib-resistant MDA-MB-468 xenograft mouse models. In addition, MT3-037 inhibited the angiogenesis and disrupted the tube formation by human endothelial cells. Our study demonstrates that MT3-037 is a potential tubulin-disrupting agent for antitumor therapy.
authors.affiliation: Chinese Medicinal Research and Development Center, China Medical University Hospital Taichung, Taiwan.
authors.forename: Ling-Chu
authors.initials: LC
authors.lastname: Chang
authors.affiliation: Graduate Institute of Cancer Biology, Center for Molecular Medicine, China Medical UniversityTaichung, Taiwan; Department of Biotechnology, Asia UniversityTaichung, Taiwan.
authors.forename: Yung-Luen
authors.initials: YL
authors.lastname: Yu
authors.affiliation: Chinese Medicinal Research and Development Center, China Medical University HospitalTaichung, Taiwan; School of Pharmacy, China Medical UniversityTaichung, Taiwan.
authors.forename: Min-Tsang
authors.initials: MT
authors.lastname: Hsieh
authors.affiliation: Stem Cell and Translational Cancer Research Center, Chang Gung Memorial Hospital at Linkou Taoyuan, Taiwan.
authors.forename: Sheng-Hung
authors.initials: SH
authors.lastname: Wang
authors.affiliation: Graduate Institute of Cancer Biology, Center for Molecular Medicine, China Medical UniversityTaichung, Taiwan; Department of Biotechnology, Asia UniversityTaichung, Taiwan.
authors.forename: Ruey-Hwang
authors.initials: RH
authors.lastname: Chou
authors.affiliation: Graduate Institute of Cancer Biology, Center for Molecular Medicine, China Medical UniversityTaichung, Taiwan; Department of Biotechnology, Asia UniversityTaichung, Taiwan.
authors.forename: Wei-Chien
authors.initials: WC
authors.lastname: Huang
authors.affiliation: Graduate Institute of Pharmaceutical Chemistry, China Medical University Taichung, Taiwan.
authors.forename: Hui-Yi
authors.initials: HY
authors.lastname: Lin
authors.affiliation: Institute of Clinical Pharmacy and Pharmaceutical Sciences, National Cheng Kung University Tainan, Taiwan.
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Hung
authors.affiliation: Graduate Institute of Pharmaceutical Chemistry, China Medical University Taichung, Taiwan.
authors.forename: Li-Jiau
authors.initials: LJ
authors.lastname: Huang
authors.affiliation: Graduate Institute of Pharmaceutical Chemistry, China Medical University Taichung, Taiwan.
authors.forename: Sheng-Chu
authors.initials: SC
authors.lastname: Kuo
keywords: CDK1; JNK; Microtubule; angiogenesis; apoptosis