title: 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.affiliation: Division of Chest Medicine, Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan, ROC.|The Center of General Education, Chia Nan University of Pharmacy & Science, Tainan, Taiwan, ROC.
authors.forename: Jiunn-Min
authors.initials: JM
authors.lastname: Shieh
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan, ROC.
authors.forename: Yen-An
authors.initials: YA
authors.lastname: Tang
authors.affiliation: Department of Pharmacology, National Cheng Kung University, Tainan, Taiwan, ROC.
authors.forename: Fu-Han
authors.initials: FH
authors.lastname: Hu
authors.affiliation: Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan, ROC.
authors.forename: Wei-Jan
authors.initials: WJ
authors.lastname: Huang
authors.affiliation: Department of Environmental and Occupational Health, National Cheng Kung University, Tainan, Taiwan, ROC.
authors.forename: Ying-Jan
authors.identifier: 0000-0002-7694-2067
authors.initials: YJ
authors.lastname: Wang
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan, ROC.
authors.forename: Jayu
authors.initials: J
authors.lastname: Jen
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan, ROC.
authors.forename: Sheng-You
authors.initials: SY
authors.lastname: Liao
authors.affiliation: Department of Pharmacology, National Cheng Kung University, Tainan, Taiwan, ROC.
authors.forename: Ying-Hung
authors.initials: YH
authors.lastname: Lu
authors.affiliation: Department of Environmental and Occupational Health, National Cheng Kung University, Tainan, Taiwan, ROC.
authors.forename: Ya-Ling
authors.initials: YL
authors.lastname: Yeh
authors.affiliation: National Institute of Environmental Health Sciences, National Health Research Institutes, Zhunan, Taiwan, ROC.
authors.forename: Tseng-Wei
authors.initials: TW
authors.lastname: Wang
authors.affiliation: National Institute of Environmental Health Sciences, National Health Research Institutes, Zhunan, Taiwan, ROC.
authors.forename: Pinpin
authors.initials: P
authors.lastname: Lin
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan, ROC.|Department of Pharmacology, National Cheng Kung University, Tainan, Taiwan, ROC.
authors.forename: Yi-Ching
authors.initials: YC
authors.lastname: Wang
mesh_terms: D000107:Acetylation; D000577:Amides / Q000737:chemistry*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics*; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects*; D000077209:Decitabine; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000577:Amides; D014408:Biomarkers, Tumor; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D012333:RNA, Messenger; D000077209:Decitabine; D001374:Azacitidine; C000360:caproamide
keywords: 5-aza-2′-deoxycytidine; Wnt signal; histone deacetylase inhibitor; lung cancer