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

Abstract

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.

• Authors: 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
• Journal: International journal of cancer (Int J Cancer) Vol. 140 Issue 10 Pg. 2375-2386 (05 15 2017) ISSN: 1097-0215 [Electronic] United States
• PMID: 28233309 (Publication Type: Journal Article)
• Copyright: © 2017 UICC.

Chemical References

• Amides
• Biomarkers, Tumor
• Histone Deacetylase Inhibitors
• Histones
• RNA, Messenger
• Decitabine
• Azacitidine
• caproamide

Topics

• Acetylation
• Amides (chemistry)
• Animals
• Apoptosis (drug effects)
• Azacitidine (analogs & derivatives, pharmacology)
• Biomarkers, Tumor (genetics)
• Blotting, Western
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, pathology)
• Cell Cycle (drug effects)
• Cell Proliferation (drug effects)
• DNA Methylation (drug effects)
• Decitabine
• Drug Synergism
• Drug Therapy, Combination
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic (drug effects)
• Histone Deacetylase Inhibitors (pharmacology)
• Histones (metabolism)
• Humans
• Immunoenzyme Techniques
• Lung Neoplasms (drug therapy, genetics, pathology)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Cells, Cultured
• Wnt Signaling Pathway (drug effects)
• Xenograft Model Antitumor Assays