ABSTRACT
N-(2-aminophenyl)-4-[N-(pyridine-3yl-methoxy-carbonyl) aminomethyl] benzamide (MS-275) is a second generation histone deacetylase (HDAC) inhibitor with significant anti-tumor efficacy currently in clinical development. We investigated the effect of MS-275 treatment on various colon cancer cell lines, as well as on mouse xenograft models derived from human colorectal cancer. MS-275 exerted strong anti-proliferative effects in five cell lines and increased the acetylation of histones 3 and 4. In vivo testing of the compound in eight different models of human colon cancer derived from primary colorectal cancers or from established cell lines revealed that five models were responders, two non-responders and one an anti-responder. Gene expression profiles were determined in order to identify genes and pathways differentially regulated upon MS-275 treatment in responder versus non-responder models. Principle component analysis revealed a correlation of the anti-tumor efficacy with the sub-clustering of the MS-275 treatment groups in 7 out of 8 models. Although the overall gene expression pattern was rather unique for each individual model, 129 genes were significantly up- and 58 genes significantly down-regulated in at least 2 out of 5 responder models in response to MS-275 treatment. We identified potential biomarkers for response to MS-275, such as PRA1, MYADM and PALM2-AKAP2 which were up-regulated in all responder models and down-regulated or unchanged in all non-responder models. Our results provide a starting point for the development of clinically relevant biomarkers for predicting a response to MS-275 and the understanding of the mode of action of this HDAC inhibitor.
Subject(s)
Antineoplastic Agents/pharmacology , Benzamides/pharmacology , Biomarkers, Tumor/metabolism , Colonic Neoplasms/drug therapy , Histone Deacetylase 2/antagonists & inhibitors , Histone Deacetylase Inhibitors/pharmacology , Histones/metabolism , Pyridines/pharmacology , Acetylation , Animals , Biomarkers, Tumor/genetics , Cell Proliferation/drug effects , Cluster Analysis , Colonic Neoplasms/enzymology , Colonic Neoplasms/genetics , Colonic Neoplasms/pathology , Dose-Response Relationship, Drug , Female , Gene Expression Profiling/methods , Gene Expression Regulation, Neoplastic/drug effects , Gene Regulatory Networks/drug effects , HCT116 Cells , HT29 Cells , Histone Deacetylase 2/genetics , Histone Deacetylase 2/metabolism , Humans , Inhibitory Concentration 50 , Mice , Mice, Nude , Oligonucleotide Array Sequence Analysis , Principal Component Analysis , Time Factors , Xenograft Model Antitumor AssaysABSTRACT
In the last few years it was found that beside genetic aberrations, epigenetic changes also play an important role in tumorigenesis. Acetylation and deacetylation of histones have been found to contribute to a significant extent to epigenetic regulation of gene expression. Analyses of various tumor models and patient samples revealed that the enzyme class of histone deacetylases is associated with many types of cancer and that, for example, over-expression of these enzymes leads to a disturbed balance between acetylation and deacetylation of histones, resulting in differences in the gene expression patterns between normal and cancer cells. Consequently, this class of enzymes has been considered as a potential target for cancer therapy. Numerous inhibitors have been identified and several are in clinical development. Although, with SAHA, one inhibitor has been approved by the FDA for a tumor indication, many open questions remain regarding the mode of action of these inhibitors. In this review, various aspects of preclinical and clinical research of the HDAC inhibitor MS-275 are described, to provide insight into the development of such a compound.
