MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo.
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.
Fournel
Marielle
M
Department of Molecular Biology, MethylGene, Inc., 7220 Frederick-Banting, Montreal, Quebec H4S 2A1, Canada.
Bonfils
Claire
C
Hou
Yu
Y
Yan
Pu Theresa
PT
Trachy-Bourget
Marie-Claude
MC
Kalita
Ann
A
Liu
Jianhong
J
Lu
Ai-Hua
AH
Zhou
Nancy Z
NZ
Robert
Marie-France
MF
Gillespie
Jeffrey
J
Wang
James J
JJ
Ste-Croix
Hélène
H
Rahil
Jubrail
J
Lefebvre
Sylvain
S
Moradei
Oscar
O
Delorme
Daniel
D
Macleod
A Robert
AR
Besterman
Jeffrey M
JM
Li
Zuomei
Z
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
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