MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo
- 1 April 2008
- journal article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Therapeutics
- Vol. 7 (4), 759-768
- https://doi.org/10.1158/1535-7163.mct-07-2026
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]Keywords
Other Versions
This publication has 48 references indexed in Scilit:
- Novel Aminophenyl Benzamide-Type Histone Deacetylase Inhibitors with Enhanced Potency and SelectivityJournal of Medicinal Chemistry, 2007
- Role for Histone Deacetylase 1 in Human Tumor Cell ProliferationMolecular and Cellular Biology, 2007
- Distinct pharmacological properties of second generation HDAC inhibitors with the benzamide or hydroxamate head groupInternational Journal of Cancer, 2007
- Histone deacetylase inhibitors for epigenetic therapy of cancerAnti-Cancer Drugs, 2007
- Will broad-spectrum histone deacetylase inhibitors be superseded by more specific compounds?Leukemia, 2006
- Anticancer activities of histone deacetylase inhibitorsNature Reviews Drug Discovery, 2006
- Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancerNature Reviews Cancer, 2006
- Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancerNature Genetics, 2005
- Upregulation and Nuclear Recruitment of HDAC1 in Hormone Refractory Prostate CancerThe Prostate, 2004
- Isolation and Characterization of Mammalian HDAC10, a Novel Histone DeacetylaseJournal of Biological Chemistry, 2002