A novel microtubule inhibitor, MT3-037, causes cancer cell apoptosis by inducing mitotic arrest and interfering with microtubule dynamics

Ling Chu Chang, Yung Luen Yu, Min Tsang Hsieh, Sheng Hung Wang, Ruey Hwang Chou, Wei Chien Huang, Hui Yi Lin, Hsin Yi Hung, Li Jiau Huang, Sheng Chu Kuo

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)747-763
Number of pages17
JournalAmerican Journal of Cancer Research
Volume6
Issue number4
Publication statusPublished - 2016

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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