Arsenic Sulfide Nanoformulation Induces Megakaryocytic Differentiation through Histone Deacetylase Inhibition

Abstract

AbstractArsenic sulfide (As4S4) is a mineral drug that can be administrated orally and has been applied in several Chinese medicine formulations for the treatment on some kinds of myeloid leukemia. However, mechanisms of As4S4 are not demonstrated adequately due to the poor water solubility of As4S4 in its original crystal form. The authors previously fabricated water dissolvable arsenic sulfide nanoformulation (ee‐As4S4), which downregulated intracellular reactive oxygen species (ROS). As ROS is closely associated with the histone deacetylase (HDAC), in this study the effect of ee‐As4S4 on the HDAC activity in chronic myeloid leukemia (CML) cells and whether the effect can induce subsequent megakaryocytic differentiation and underlying mechanisms are investigated. Results show that ee‐As4S4 inhibits HDAC activity in CML cells, resulting in the suppression of cellular respiration. The inhibition of HDAC activity also leads to the transcriptional activation of RUNX1, which induces megakaryocytic differentiation in CML cell lines, evidenced by the significantly multiple nuclei and giant nuclear structure, upregulation of CD41a and the increased phosphorylation of ERK1/2. In conclusion, ee‐As4S4 is able to inhibit HDAC activity, and therefore induce significant megakaryocytic differentiation in CML cells through RUNX1‐dependent pathways, which suggests its clinical potential as a complementary drug option for CML patients.