MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity <i>in vitro</i> and <i>in vivo</i>

Molecular Cancer Therapeutics - Tập 7 Số 4 - Trang 759-768 - 2008
Marielle Fournel1, Claire Bonfils1, Yu Hou1, Pu Yan1, Marie-Claude Trachy-Bourget1, Ann Kalita1, Jianhong Liu1, Aihua Lu2, Nancy Z. Zhou3, Marie‐France Robert4, Jeffrey Gillespie5, Jinru Wang5, Hélène Ste-Croix4, Jubrail Rahil2, Sylvain Lefèbvre4, Oscar Moradei3, Daniel Delorme3, A. Robert MacLeod4, Jeffrey M. Besterman1,2,3,4,5, Zuomei Li1
11Molecular Biology, Departments of
22Lead Discovery,
33Medicinal Chemistry,
44Cell Biology and Pharmacology, and
55Pharmacokinetics, MethylGene, Inc., St. Laurent, Quebec, Canada

Tóm tắt

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. [Mol Cancer Ther 2008;7(4):759–68]

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