title: Antitumor effects of a novel histone deacetylase inhibitor NK-HDAC-1 on breast cancer.
abstract: Histone deacetylases (HDACs) are overexpressed in various types of primary human cancer and have become attractive targets for cancer therapy. We designed and synthesized a series of new class of HDAC inhibitors (HDACi). Among these, S-(E)-3-(1-(1-(benzo[d]oxazol-2-yl)-2-methylpropyl)-1H-1,2,3-triazol-4-yl)-N-hydroxyacrylamide (NK-HDAC-1) showed potent antitumor activity. In the present study, we examined the antitumor effects of NK-HDAC-1 on breast cancer in vitro and in vivo. The inhibitory effects of NK-HDAC-1 on HDAC enzyme activity and cell growth were more potent compared to suberoylanilide hydroxamic acid (SAHA). NK-HDAC-1 caused G1 cell cycle arrest at concentrations below 0.2 µM and G2/M arrest at concentrations above 0.4 µM through p21 upregulation and cyclin D1 downregulation. NK-HADC-1 induced hyperacetylation of histone H3 and H4 around the promoter region of p21. NK-HDAC-1 promoted apoptosis in MDA-MB-231 breast cancer cells by activating both the intrinsic and the extrinsic pathway NK-HDAC-1 at doses of 3, 10 and 30 mg/kg reduced the tumor volume in MDA-MB-231 xenografts by 25.9, 48.8 and 63.6%, respectively. The results suggested that NK-HDAC-1 may be a promising therapeutic candidate in treating human breast cancer.
authors.affiliation: National Glycoengineering Research Center and School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong 250012, P.R. China.
authors.forename: Zhong-Hua
authors.initials: ZH
authors.lastname: Li
authors.forename: Xiao-Bing
authors.initials: XB
authors.lastname: Zhang
authors.forename: Xi-Qian
authors.initials: XQ
authors.lastname: Han
authors.forename: Cong-Ran
authors.initials: CR
authors.lastname: Feng
authors.forename: Feng-Shan
authors.initials: FS
authors.lastname: Wang
authors.forename: Peng George
authors.initials: PG
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
authors.forename: Yi-Kang
authors.initials: YK
authors.lastname: Shi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001583:Benzoxazoles / Q000009:adverse effects / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000096:biosynthesis; D015536:Down-Regulation; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D015854:Up-Regulation; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
chemical_list: C574634:3-(1-(1-(benzo(d)oxazol-2-yl)-2-methylpropyl)-1H-1,2,3-triazol-4-yl)-N-hydroxyacrylamide; D001583:Benzoxazoles; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D019938:Cyclin D1; D000077337:Vorinostat