The newly synthesized 2-arylnaphthyridin-4-one, CSC-3436, induces apoptosis of non-small cell lung cancer cells by inhibiting tubulin dynamics and activating CDK1

Ling Chu Chang, Yung Luen Yu, Chin Yu Liu, Yung Yi Cheng, Ruey Hwang Chou, Min Tsang Hsieh, Hui Yi Lin, Hsin Yi Hung, Li Jiau Huang, Yang Chang Wu, Sheng Chu Kuo

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

Abstract

Purpose: To investigate the anticancer therapeutic potential of a new synthetic compound, 2-(3-hydroxyphenyl)-5-methylnaphthyridin-4-one (CSC-3436), on non-small cell lung cancer (NSCLC) cells. Methods: Cell viability was determined by MTT assay. Cell cycle distribution was assessed by propidium iodide staining and subjected to flow cytometry analysis. Protein expression was detected by western blot analysis. Pharmacological inhibitors and shRNAs were applied to examine the possible pathways involved CSC-3436-inhibited viability of NSCLC cells. Results: CSC-3436 decreased NSCLC cell viability by inducing apoptosis. In vivo and in vitro tubulin polymerization assays revealed that CSC-3463 caused tubulin depolymerization by directly binding to the colchicine-binding site. Furthermore, CSC-3436 caused the mitotic arrest with a marked activation of cyclin-dependent kinase 1 (CDK1) and increased the expression of phospho-Ser/Thr-Pro mitotic protein monoclonal 2. The CDK1 inhibitor, roscovitine, reversed the CSC-3436-induced upregulation of CDK1 activity as well as the mitotic arrest. DNA damage response kinases, including ataxia telangiectasia mutated (ATM), ATM and Rad3-related, DNA-dependent protein kinase, checkpoint kinase 1, and checkpoint kinase 2, were phosphorylated and activated by CSC-3436. c-Jun N-terminal kinase was activated by CSC-3436 and involved in the regulation of mitotic arrest and apoptosis. CSC-3436-induced apoptosis was accompanied by the activation of pro-apoptotic factors FADD, TRADD, and RIP and the inactivation of anti-apoptotic proteins Bcl-2 and Bcl-xL, resulting in the cleavage and subsequent activation of caspases. Conclusions: Our results reveal the cellular events in which CSC-3436 induces tumor cell death and demonstrate that CSC-3436 is a potential tubulin-disrupting agent for antitumor therapy against NSCLC.

Original languageEnglish
Pages (from-to)1303-1315
Number of pages13
JournalCancer Chemotherapy and Pharmacology
Volume75
Issue number6
DOIs
Publication statusPublished - 2015 Jun 26

All Science Journal Classification (ASJC) codes

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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