Entinostat treatment causes hypophosphatemia and hypocalcemia by increasing Fgf23 in mice

Abstract

Entinostat, a class I HDACs-selective inhibitor, is currently in clinical trials for treating cancers. In some of the trials, Entinostat treatment frequently causes hypophosphatemia and/or hypocalcemia. Moreover, the effect of Entinostat treatment on bone remains incompletely understood. In this study, we found that Entinostat treatment mildly increased the trabecular but not cortical bone volume, without compromising the bone strength, the numbers of Runx2-positive cells and TRAP-positive cells, and the serum levels of P1NP and TRAP-5b. Entinostat treatment significantly reduced the level of Runx2 mRNA but not Runx2 protein, and as a trend attenuated Ctsk expression. Furthermore, Entinostat treatment did not enhance MC3T3-E1 cell proliferation in vitro. These findings suggest that Entinostat increases trabecular bone volume not by regulating osteoblastogenesis or osteoclastogenesis, but possibly by attenuating the resorption capacity. Unexpectedly, Entinostat treatment increased the expression of Fgf23, whose protein is a hormone that regulates the serum level of phosphate (Pi). Meanwhile, Entinostat treatment increased the serum level of the active form (intact) Fgf23 and reduced that of Pi and calcium (Ca) as well. This study raised a concern about the anabolic effects of Entinostat in bone, and demonstrated that Entinostat treatment causes hypophosphatemia and hypocalcemia by upregulating Fgf23 mRNA and increasing intact Fgf23 protein in serum.