Efficacy of MS-275, a selective inhibitor of class I histone deacetylases, in human colon cancer models

Abstract

Abstract. N-(2-aminophenyl)-4-[N-(pyridine-3yl-methoxycarbonyl) 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 downregulated 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.

Transcriptomic and Epigenomic Profiling of Histone Deacetylase Inhibitor Treatment Reveals Distinct Gene Regulation Profiles Leading to Impaired Neutrophil Development

“…The benzamide MS‐275 (entinostat) selectively inhibits class I HDACs, with a preference for HDAC1 and to a lesser extent HDAC3, while the hydroxamic acid SAHA non‐selectively inhibits class I/II HDACs 37 . Although their differences in inhibitory selectivity, both compounds are known to increase acetylation on histones H3 and H4, induce p21 expression and activate apoptotic pathways in malignant cells 38–42 …”

“…37 Although their differences in inhibitory selectivity, both compounds are known to increase acetylation on histones H3 and H4, induce p21 expression and activate apoptotic pathways in malignant cells. [38][39][40][41][42] In this study, we investigated the effects of HDAC inhibition on normal hematopoiesis using two distinct HDACi, MS-275 and SAHA. We performed transcriptomic, epigenomic, functional and morphological analysis during neutrophil development in the presence and absence of the HDACi MS-275 and SAHA.…”

The Class I HDAC Inhibitor, MS-275, Prevents Oxaliplatin-Induced Chronic Neuropathy and Potentiates Its Antiproliferative Activity in Mice

“…Consistently, we observed that T84 cells, that do not express p53 [ 58 ] demonstrated a strong resistance, whereas HT29, which expresses p53, was highly sensitive toward the antiproliferative effect of MS-275. HT29 was previously shown to be a responder to MS-275, which might increase the adhesive properties of these cells, thus preventing their metastatic spread and immune escape [ 59 ]. On the contrary, T84 cells can thus be considered as a weak or non-responder, as it has been shown for other CRC cell lines for which MS-275 induced downregulation of genes involved in cell adhesion [ 59 ].…”

“…HT29 was previously shown to be a responder to MS-275, which might increase the adhesive properties of these cells, thus preventing their metastatic spread and immune escape [ 59 ]. On the contrary, T84 cells can thus be considered as a weak or non-responder, as it has been shown for other CRC cell lines for which MS-275 induced downregulation of genes involved in cell adhesion [ 59 ]. Whether such genes regulation also occurs in T84 cells will be of interest in order to define biomarkers to predict the response to MS-275.…”

Combining Oncolytic Viruses and Small Molecule Therapeutics: Mutual Benefits

“…This discrepancy in modulating the adaptive immune response can be related to the differences in HDAC targets of the different HDIs. Trichostatin A inhibits class I and II HDACS [ 135 ], Entinostat inhibits class I HDACs [ 136 ], whereas vorinostat and to a lesser extent valproate are pan-HDAC inhibitors [ 137 , 138 ]. Among the HDIs vorinostat is considered the more potent candidate for combination with OVs.…”