The NF (Nuclear factor)‐κB inhibitor parthenolide interacts with histone deacetylase inhibitors to induce MKK7/JNK1‐dependent apoptosis in human acute myeloid leukaemia cells

Summary Interactions between the nuclear factor (NF)‐κB inhibitor parthenolide and the pan‐histone deacetylase inhibitors (HDACIs) vorinostat and LBH589 were investigated in human acute myeloid leukaemia (AML) cells, including primary AML blasts. Co‐administration of parthenolide blocked HDACI‐mediated phosphorylation/activation of IKK and RelA/p65 in association with increased JNK1 activation in various AML cell types. These events were accompanied by an increase in apoptosis in multiple AML cell lines (e.g. U937, HL‐60, NB4, MV‐4‐11, and MOLM‐13). Significantly, parthenolide also increased HDACI‐mediated cell death in haematopoietic cells transduced with the MLL ‐ MLLT1 fusion gene, which exhibit certain leukaemia‐initiating cell characteristics, as well as primary AML blasts. Exposure to parthenolide/HDACI regimens clearly inhibited the growth of AML‐colony‐forming units but was relatively sparing toward normal haematopoietic progenitors. Notably, blockade of c‐Jun N‐terminal kinase (JNK) signalling by either pharmacological inhibitors or genetic means (e.g. dominant‐negative JNK1 or JNK1 shRNA) diminished parthenolide/HDACI‐mediated lethality. Moreover, dominant‐negative MKK7, but not dominant‐negative MKK4/SEK1, blocked JNK1 activation and apoptosis induced by parthenolide/HDACI regimens. Together, these findings indicate that parthenolide potentiates HDACI lethality in human AML cells through a process involving NF‐κB inhibition and subsequent MKK7‐dependent activation of the SAPK/JNK pathway. They also raise the possibility that this strategy may target leukaemic progenitor cells.