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 isotypeselective HDAC inhibitor. We have developed an isotypeselective 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]

Combinations of DNA Methyltransferase and Histone Deacetylase Inhibitors Induce DNA Damage in Small Cell Lung Cancer Cells: Correlation of Resistance with IFN-Stimulated Gene Expression

“…2). Despite evidence that apoptosis induced by HDAC inhibitors can be increased by 5-AZA-dC (16,21,39), our data suggested that induction of apoptosis was not the primary mechanism for synergy between 5-AZA-dC and MGCD0103 in SCLC cells.…”

“…Acetylation of histones affects the transcription of genes by modification of chromatin structure and is dependent on the contrasting actions of histone acetyltransferase and HDAC (13). Like DNMT inhibitors, HDAC inhibitors exhibit their antineoplastic effects by enhancing differentiation, apoptosis, growth inhibition, cell cycle arrest, and cell death through DNA damage by transcriptional modulation of antiapoptotic and proapoptotic genes (14)(15)(16)(17)(18).…”

Histone Deacetylases as New Therapeutic Targets in Triple-negative Breast Cancer: Progress and Promises

“…Mocetinostat is a class I HDAC inhibitor that is associated with the reversion of cardiac fibrosis (91). Recently, mocetinostat was reported to have promising antitumor activities against various types of cancer cell lines and tumor xenografts in nude mice, as it is related to apoptosis (92)(93)(94). A study showed that mocetinostat inhibits the growth of colon cancer cells via the up-regulation of WNT ligand DKK-1 expression (95).…”

“…Also, in B-cell chronic lymphocytic leukemia cells, it has been shown to lead to apoptosis, as it decreases the expression of Mcl-1 protein and it induces Bax translocation to mitochondria (96). Another study has shown that mocetinostat inhibits the proliferation of prostate cancer cells (93).…”

Inhibition of class I HDACs abrogates the dominant effect of MLL-AF4 by activation of wildtype MLL

“…Transfected cells were then incubated with different HDACi that display distinct inhibitory profiles for the various HDAC isoforms: MC-1568 is an inhibitor of class IIa HDACs; Apicidin acts on HDAC1, HDAC2, HDAC3 and HDAC8; MS-275 (Entinostat) preferentially inhibits HDAC1, but also inhibits HDAC2 and HDAC3 at micromolar concentrations; PCI-34051 is a known HDAC8 inhibitor; Mocetinostat (MGCD0103) is an HDAC1, HDAC2 and HDAC3 inhibitor; and Droxinostat is an HDAC3, HDAC6 and HDAC8 inhibitor. [24][25][26][27][28] Similar to TSA, all tested inhibitors that interfere with HDACs 1-3 strongly increased ALOX5 promoter activity, whereas the inhibition of class IIa HDACs or HDAC8 had no effect (Figures 4a and b). Co-transfection of AF4-MLL leads to similar promoter activity as pTarget (negative control), suggesting that in contrast to MLL and MLL-AF4, the AF4-MLL fusion protein does not activate the basal ALOX5 promoter.…”