Inactivation of JAK/STAT Cell Signaling by SK-7041, a Novel HDAC Inhibitor, Effectively Inhibits Growth of Acute Myeloid Leukemia Cells

Abstract

Activation of the JAK/STAT pathway appears common in AML, occurring in up to 70% of AML patients. Therefore, JAK/STAT signal inhibitors are promising as candidate anti-cancer agents in AML. Recently, we reported that SK-7041, an HDAC inhibitor, inhibited the growth of AML cells via activation of caspase-3 and down-regulation of cyclin D1. These findings lead us to further examine whether SK-7041 inhibits the growth of KG1 AML cells via inactivation of JAK/STAT signals. Multi-immunoblotting technique (Kinetworks™ analysis) showed that expression of p-STAT-3, p-STAT-5, and p-Erk was down-regulated in KG1 cells treated with SK-7041. These results were confirmed by individual western blot analysis. In addition, IL-6-induced activation of STAT-3 and Erk was inhibited by treatment of SK-7041. Combined treatment of SK-7041 and JAK inhibitor (AG490) showed additive anti-leukemic effect as evidenced by caspase-3 activation, down-regulation of cyclin D1 (cMYC), and inhibition of phosphorylation of STATs (−1, −3). These results suggest that HDAC inhibitor, SK-7041, inhibited AML cell growth via inactivation of JAK/STATs pathway.