The Crucial Role of ROS-HO-1 Dependent Apoptosis Induced By Pan-HDACi in T-Cell Acute Lymphoblastic Leukemia

Histone hypoacetylation occurs in many hematological malignances and histone deacetylase inhibitors (HDACi) is a promising approach to treat hematological malignances. The purpose of our study was to further investigate the mechanisms and efficiency of pan-HDAC inhibition (AR-42) in primary human TALL cells and T-ALL cell line. Our previous study demonstrated significantly increased mRNA and protein expression of HDAC1 HDAC2 HDAC3 HDAC7 and HO-1 in T-ALL patients( p <0.01); the expression of HDAC1and HDAC2 and HO-1 were associated with the risk stratification. Furthermore HO-1 overexpression was mediated by constitutively activated NF-κB, which were confirmed by EMSA, immunofluorescence and immunoblotting. In present study, primary cell of 25 T-ALL patients and Jurkat were treated with AR-42, and cell viability, apoptosis, cell cycle, mitochondrial membrane potential(MMP) and effects on signaling pathways were examined. Our data showed AR-42 was cytotoxic to T-ALL cells with IC50 values of 0.325±0.082 and 0.296±0.064μM for T-ALL primary cell and Jurkat; AR-42 arrested Jurkat cells at G0/G1 phase with the increasing expression of p21; AR-42 induced apoptosis with cleavage of caspases3,8 and 9, and cell apoptosis was largely prevented by caspase inhibition (Z-VAD-FMK). AR-42 induced apoptosis through an increase in the ROS production and the disruption of mitochondrial membrane potential, and cell apoptosis induced by AR-42 was significantly diminished by ROS scavengers NAC (N-acetylcysteine). AR-42 downregulated the expression of HO-1 and inhibited activation of NF-κB. Overexpression of HO-1 by a lentivirus construct partly prevent apoptosis induced by AR-42. Together, these data demonstrate that AR-42 can induce caspase-dependent apoptosis mainly through ROS-(NF-κB)- (HO-1) pathway in T-cell acute lymphoblastic leukemia.