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

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