title: MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo.
abstract: Nonselective inhibitors of human histone deacetylases (HDAC) are known to have antitumor activity in mice in vivo, and several of them are under clinical investigation. The first of these, Vorinostat (SAHA), has been approved for treatment of cutaneous T-cell lymphoma. Questions remain concerning which HDAC isotype(s) are the best to target for anticancer activity and whether increased efficacy and safety will result with an isotype-selective HDAC inhibitor. We have developed an isotype-selective HDAC inhibitor, MGCD0103, which potently targets human HDAC1 but also has inhibitory activity against HDAC2, HDAC3, and HDAC11 in vitro. In intact cells, MGCD0103 inhibited only a fraction of the total HDAC activity and showed long-lasting inhibitory activity even upon drug removal. MGCD0103 induced hyperacetylation of histones, selectively induced apoptosis, and caused cell cycle blockade in various human cancer cell lines in a dose-dependent manner. MGCD0103 exhibited potent and selective antiproliferative activities against a broad spectrum of human cancer cell lines in vitro, and HDAC inhibitory activity was required for these effects. In vivo, MGCD0103 significantly inhibited growth of human tumor xenografts in nude mice in a dose-dependent manner and the antitumor activity correlated with induction of histone acetylation in tumors. Our findings suggest that the isotype-selective HDAC inhibition by MGCD0103 is sufficient for antitumor activity in vivo and that further clinical investigation is warranted.
authors.affiliation: Department of Molecular Biology, MethylGene, Inc., 7220 Frederick-Banting, Montreal, Quebec H4S 2A1, Canada.
authors.forename: Marielle
authors.initials: M
authors.lastname: Fournel
authors.forename: Claire
authors.initials: C
authors.lastname: Bonfils
authors.forename: Yu
authors.initials: Y
authors.lastname: Hou
authors.forename: Pu Theresa
authors.initials: PT
authors.lastname: Yan
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Trachy-Bourget
authors.forename: Ann
authors.initials: A
authors.lastname: Kalita
authors.forename: Jianhong
authors.initials: J
authors.lastname: Liu
authors.forename: Ai-Hua
authors.initials: AH
authors.lastname: Lu
authors.forename: Nancy Z
authors.initials: NZ
authors.lastname: Zhou
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Robert
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Gillespie
authors.forename: James J
authors.initials: JJ
authors.lastname: Wang
authors.forename: Hélène
authors.initials: H
authors.lastname: Ste-Croix
authors.forename: Jubrail
authors.initials: J
authors.lastname: Rahil
authors.forename: Sylvain
authors.initials: S
authors.lastname: Lefebvre
authors.forename: Oscar
authors.initials: O
authors.lastname: Moradei
authors.forename: Daniel
authors.initials: D
authors.lastname: Delorme
authors.forename: A Robert
authors.initials: AR
authors.lastname: Macleod
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Besterman
authors.forename: Zuomei
authors.initials: Z
authors.lastname: Li
mesh_terms: D000107:Acetylation; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000493:pharmacokinetics / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D007527:Isoenzymes; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays; D000099186:Histone Deacetylase 3
chemical_list: D001549:Benzamides; D004791:Enzyme Inhibitors; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006877:Hydroxamic Acids; D007527:Isoenzymes; D011743:Pyrimidines; D012097:Repressor Proteins; D000077337:Vorinostat; D000099186:Histone Deacetylase 3; C523184:mocetinostat; C110550:HDAC1 protein, human; C462506:HDAC11 protein, human; C533424:Hdac2 protein, mouse