title: Potential anti-cancer activity of N-hydroxy-7-(2-naphthylthio) heptanomide (HNHA), a histone deacetylase inhibitor, against breast cancer both in vitro and in vivo.
abstract: Histone deacetylase (HDAC) is an attractive target for cancer therapy because it plays a key role in gene expression and carcinogenesis. N-hydroxy-7-(2-naphthylthio) heptanomide (HNHA) is a novel synthetic HDAC inhibitor (HDACI) that shows better pharmacological properties than a known HDACI present in the human fibrosarcoma cell: suberoylanilide hydroxamic acid (SAHA). Here, we investigate the anti-cancer activity of HNHA against breast cancer both in vitro and in vivo. HNHA arrested the cell cycle at the G(1) /S phase via p21 induction, which led to profound inhibition of cancer cell growth in vitro. In addition, HNHA-treated cells showed markedly decreased levels of VEGF and HIF-1α than SAHA and fumagillin (FUMA) when accompanied by increased histone acetylation. HNHA significantly inhibited tumor growth in an in vivo mouse xenograft model. HNHA-treated mice survived significantly longer than SAHA- and FUMA-treated mice. Dynamic MRI showed significantly decreased blood flow in the HNHA-treated mice, implying that HNHA inhibits tumor neovascularization. This finding was accompanied by marked reductions of proangiogenic factors and significant induction of angiogenesis inhibitors in tumor tissues. We have shown that HNHA is an effective anti-tumor agent in breast cancer cells in vitro and in breast cancer xenografts in vivo. Collectively, these findings indicate that HNHA may be a potent anti-cancer agent against breast cancer due to its multi-faceted inhibition of HDAC activity, as well as anti-angiogenesis activity.
authors.affiliation: Brain Korea 21 Project for Medical Science, Department of Surgery, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Ki Cheong
authors.initials: KC
authors.lastname: Park
authors.forename: Seung Won
authors.initials: SW
authors.lastname: Kim
authors.forename: Ji Hyun
authors.initials: JH
authors.lastname: Park
authors.forename: Eun Hye
authors.initials: EH
authors.lastname: Song
authors.forename: Jeong Won
authors.initials: JW
authors.lastname: Yang
authors.forename: Hyun Joo
authors.initials: HJ
authors.lastname: Chung
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Jung
authors.forename: Jin Suck
authors.initials: JS
authors.lastname: Suh
authors.forename: Ho Jeong
authors.initials: HJ
authors.lastname: Kwon
authors.forename: Seung Hoon
authors.initials: SH
authors.lastname: Choi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007150:Immunohistochemistry; D051379:Mice; D009281:Naphthalenes / Q000494:pharmacology*; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C520433:N-hydroxy-7-(2-naphthylthio)heptanamide; D009281:Naphthalenes