Apicidin potentiates the imatinib‐induced apoptosis of Bcr–Abl‐positive human leukaemia cells by enhancing the activation of mitochondria‐dependent caspase cascades

Summary Apicidin, a histone deacetylase inhibitor, is a novel cyclic tetrapeptide with potent antiproliferative activity against various cancer cells. We examined whether apicidin potentiates the imatinib‐induced apoptosis of Bcr–Abl‐positive human leukaemia cells. In K562 cells, the co‐administration of minimally toxic concentrations of imatinib and apicidin (imatinib/apicidin) for 48 h produced a marked increase in mitochondrial damage, processing of caspase cascades and apoptosis. Similar results were observed in leukaemic blasts obtained from patients with chronic myeloid leukaemia in blast crisis. Imatinib/apicidin co‐treatment for 48 h resulted in a near complete loss of the full‐length XIAP (X‐linked inhibitor of apoptosis) protein, with a corresponding increase in the 29‐kDa XIAP cleavage product. Both the degradation of XIAP and increased release of second mitochondria‐derived activator of caspase/direct IAP‐binding protein with low pI (Smac/DIABLO) into the cytosol were abrogated by pretreatment with the caspase‐3 inhibitor DEVD‐CHO. Imatinib/apicidin co‐treatment for 48 h produced a prominent decrease in Bcr–Abl protein levels in a caspase‐dependent manner. In summary, these data indicate that apicidin potentiates the imatinib‐induced apoptosis of Bcr–Abl‐positive leukaemia cells through the enhanced activation of the mitochondria‐dependent caspase cascades, accompanied by caspase‐dependent downregulation of Bcr–Abl and XIAP. These findings generate a rationale for further investigation of apicidin and imatinib as a potential therapeutic strategy in Bcr–Abl‐positive leukaemias.