A histone deacetylase inhibitor enhances expression of genes inhibiting Wnt pathway and augments activity of DNA demethylation reagent against nonsmall-cell lung cancer

Jiunn Min Shieh, Yen An Tang, Fu Han Hu, Wei Jan Huang, Ying Jan Wang, Jayu Jen, Sheng You Liao, Ying Hung Lu, Ya Ling Yeh, Tseng Wei Wang, Pinpin Lin, Yi Ching Wang

研究成果: Article

11 引文 斯高帕斯(Scopus)

摘要

Development of new inhibitors targeting histone deacetylases (HDACs) with improved efficacy for solid tumor therapy is urgently needed. Here, we report the development of a novel HDAC inhibitor TMU-35435 and verify it as a single agent and in combination treatment with DNA demethylation reagent 5-aza-2′-deoxycytidine (5-aza-dC) in lung cancer preclinical models. TMU-35435 exerted cancer-specific cytotoxicity via mitochondria-mediated apoptosis. Expression microarrays revealed a unique TMU-35435-induced gene networks enriched in biological processes, including “negative regulation of cell proliferation” and “Wnt receptor signaling pathway” compared to FDA-approved HDAC inhibitor SAHA. TMU-35435 inhibited tumor growth with good pharmacokinetic properties and safety features in lung orthotopic and subcutaneously implanted xenograft models. TMU-35435 and 5-aza-dC showed synergistic antitumor effects through reactivation of tumor suppressor genes and those genes encoding negative regulators of Wnt signaling pathway in vitro and in vivo. Some genes showed additive inhibition of DNA methylation upon TMU-35435 and 5-aza-dC combined treatment. Our findings suggested that TMU-35435 is a potential HDAC inhibitor for lung cancer treatment as a single agent and in combination with 5-aza-dC.

原文English
頁(從 - 到)2375-2386
頁數12
期刊International Journal of Cancer
140
發行號10
DOIs
出版狀態Published - 2017 五月 15

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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