The NF (Nuclear factor)-κB inhibitor parthenolide interacts with histone deacetylase inhibitors to induce MKK7/JNK1-dependent apoptosis in human acute myeloid leukaemia cells.
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.
Dai
Yun
Y
Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University, 401 College Street, Richmond, VA 23298, USA.
Guzman
Monica L
ML
Chen
Shuang
S
Wang
Li
L
Yeung
Sin-Kei
SK
Pei
Xin-Yan
XY
Dent
Paul
P
Jordan
Craig T
CT
Grant
Steven
S
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
D056572:Histone Deacetylase Inhibitors; D016328:NF-kappa B; D012717:Sesquiterpenes; C002669:parthenolide; D048031:JNK Mitogen-Activated Protein Kinases