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.