The tyrphostin adaphostin interacts synergistically with proteasome inhibitors to induce apoptosis in human leukemia cells through a reactive oxygen species (ROS)-dependent mechanism.
Interactions between the tyrphostin adaphostin and proteasome inhibitors (eg, MG-132 and bortezomib) were examined in multiple human leukemia cell lines and primary acute myeloid leukemia (AML) specimens. Cotreatment of Jurkat cells with marginally toxic concentrations of adaphostin and proteasome inhibitors synergistically potentiated mitochondrial damage (eg, cytochrome c release), caspase activation, and apoptosis. Similar interactions occurred in other human leukemia cell types (eg, U937, HL-60, Raji). These interactions were associated with a marked increase in oxidative damage (eg, ROS generation), down-regulation of the Raf/MEK/ERK pathway, and JNK activation. Adaphostin/MG-132 lethality as well as mitochondrial damage, down-regulation of Raf/MEK/ERK, and activation of JNK were attenuated by the free-radical scavenger NAC, suggesting that oxidative damage plays a functional role in antileukemic effects. Ectopic expression of Raf-1 or constitutively active MEK/ERK or genetic interruption of the JNK pathway significantly diminished adaphostin/MG-132-mediated lethality. Interestingly, enforced Raf or MEK/ERK activation partially diminished adaphostin/MG-132-mediated ROS generation, suggesting the existence of an amplification loop. Finally, the adaphostin/MG-132 regimen displayed similar toxicity toward 5 primary AML samples but not normal hematopoietic progenitors (eg, bone marrow CD34+ cells). Collectively, these findings suggest that potentiating oxidative damage by combining adaphostin with proteasome inhibitors warrants attention as an antileukemic strategy.
Dasmahapatra
Girija
G
Department of Medicine, Virginia Commonwealth University, Richmond, VA, USA.
Rahmani
Mohamed
M
Dent
Paul
P
Grant
Steven
S
D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology; D019169:Jurkat Cells; D007938:Leukemia / Q000473:pathology*; D018384:Oxidative Stress; D061988:Proteasome Inhibitors; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D020032:Tyrphostins / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D006873:Hydroquinones; C404397:NSC 680410; D061988:Proteasome Inhibitors; D017382:Reactive Oxygen Species; D020032:Tyrphostins; D000218:Adamantane