acy-1215 and entinostat

Myeloid-derived suppressor cells (MDSCs) are widely implicated in negative regulation of immune responses in cancer. Inhibition of class I histone deacetylases (HDAC) with entinostat has anti-MDSC activity. However, as single agent, it did not delay tumor growth in EL4 and LLC tumor models. Here, we found that entinostat reduced immune suppressive activity of only one type of MDSC-polymorphonuclear, PMN-MDSC, whereas it had no effect on monocytic M-MDSC or macrophages. M-MDSC had high amount of class II HDAC-HDAC6, which was further increased after the treatment of mice with entinostat. Inhibition of HDAC6 with ricolinostat reduced suppressive activity of M-MDSC, but did not affect PMN-MDSC or delayed tumor growth. However, combination of entinostat and ricolinostat abrogated suppressive activity of both populations of MDSC and substantially delayed tumor progression. Thus, inactivation of MDSC required targeting of both major subsets of these cells via inhibitors of class I and class II HDAC.

Topics: Animals; Benzamides; Cell Line, Tumor; Female; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxamic Acids; Mice; Mice, Inbred C57BL; Monocytes; Myeloid Cells; Myeloid-Derived Suppressor Cells; Neoplasms; Pyridines; Pyrimidines

Class-selective histone deacetylase (HDAC) inhibitors were designed to improve safety profiles and therapeutic effectiveness in the treatment of multiple cancers relative to pan-HDAC inhibitors. However, the underlying mechanisms for their therapeutic and cardiotoxic potentials remain poorly understood. Cardiac sodium currents (I

Topics: Animals; Benzamides; Blotting, Western; Cells, Cultured; Connexin 43; Gap Junctions; Histone Deacetylase Inhibitors; Hydroxamic Acids; Indoles; Mice; Mice, Inbred C57BL; Myocytes, Cardiac; NAV1.5 Voltage-Gated Sodium Channel; Panobinostat; Patch-Clamp Techniques; Pyridines; Pyrimidines