[Adaphostin interacts synergistically with proteasome inhibitors to induce apoptosis in human leukemia cells]
>>Blood. 2005 Sep 15; [Epub ahead of print]
The tyrphostin adaphostin interacts synergistically with proteasome inhibitors to induce apoptosis in human leukemia cells through a reactive oxygen species (ROS)-dependent mechanism.
Dasmahapatra G, Rahmani M, Dent P, Grant S.
Department of Medicine, Virginia Commonwealth University, Richmond, VA, USA.
Interactions between the tyrphostin adaphostin and proteasome inhibitors (e.g., MG-132 and Bortezomib) were examined in multiple human leukemia cell lines and primary AML specimens. Co-treatment of Jurkat cells with marginally toxic concentrations of adaphostin and proteasome inhibitors synergistically potentiated mitochondrial damage (e.g., cytochrome c release), caspase activation, and apoptosis. Similar interactions occurred in other human leukemia cell types (e.g., U937, HL-60, Raji). These interactions were associated with a marked increase in oxidative damage (e.g., 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 (e.g., bone marrow CD34(+) cells). Collectively, these findings suggest that potentiating oxidative damage by combining adaphostin with proteasome inhibitors warrants attention as an antileukemic strategy.<<
To quote several boxers: "Combinations, combinations . . . "
Cheers, Tuck |
