title: Antitumor effects of a novel sulfur-containing hydroxamate histone deacetylase inhibitor H40.
abstract: Histone deacetylase (HDAC) inhibitors are among the most promising targeted anticancer agents and are potent inducers of growth arrest, differentiation, and/or apoptotic cell death of transformed cells. In this study, antitumor effects of a novel sulfur-containing hydroxamate HDAC inhibitor, H40, were observed and compared with a typical HDAC inhibitor SAHA. In biochemical HDAC assay, H40 showed a potent HDAC inhibition. It induced histone H3 hyperacetylation, correlating with inhibition of cancer cell proliferation, induction of cell differentiation and cell cycle blockage. A broad cytotoxicity was observed across cell lines from different tumor entities. The autophagy rather than apoptosis inducing activity for both H40 and SAHA was observed in prostate cancer PC-3M cells. HDAC inhibitor-induced p21(CIP/WAF1) expression was evident in PC-3M and HL-60 cell lines. The in vivo efficacy of H40 against a murine prostate carcinoma TRAMP-C2 was compared with that of SAHA, which showed that H40 exerted a favorable antitumor action when only administered twice a week. We conclude that H40 might have clinical value in cancer chemotherapy and warrants further investigation in this regard.
authors.affiliation: Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Long
authors.forename: Jinyan
authors.initials: J
authors.lastname: Zhao
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yan
authors.forename: Ziliang
authors.initials: Z
authors.lastname: Liu
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
mesh_terms: D000107:Acetylation; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000032:analysis / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D000970:Antineoplastic Agents; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids