Heme oxygenase-1 reduces the sensitivity to imatinib through nonselective activation of histone deacetylases in chronic myeloid leukemia

Abstract

Resistance towards imatinib (IM) remains troublesome in treating many chronic myeloid leukemia (CML) patients. Heme oxygenase-1 (HO-1) is a key enzyme of antioxidative metabolism in association with cell resistance to apoptosis. Our previous studies have shown that overexpression of HO-1 resulted in resistance development to IM in CML cells, while the mechanism remains unclear. In the current study, the IM-resistant CML cells K562R indicated upregulation of some of the histone deacetylases (HDACs) compared with K562 cells. Therefore, we herein postulated HO-1 was associated with HDACs. Silencing HO-1 expression in K562R cells inhibited the expression of some HDACs, and the sensitivity to IM was increased. K562 cells transfected with HO-1 resisted IM and underwent obvious some HDACs. These findings related to the inhibitory effects of high HO-1 expression on the reactive oxygen species (ROS) signaling pathway that negatively regulated HDACs. Increased expression of HO-1 activated HDACs by inhibiting ROS production. In summary, HO-1, which is involved in the development of drug resistance in CML cells by regulating the expression of HDACs, is probably a novel target for improving CML therapy.

Keywords: AR-42; HDACs; HO-1; ROS; chronic myeloid leukemia.