Adaphostin Interacts Synergistically with Bortezomib in Acute Leukemias

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Blood First Edition Paper, prepublished online September 15, 2005;

Submitted June 15, 2005

Accepted August 26, 2005

The tyrphostin adaphostin interacts synergistically with proteasome

inhibitors to induce apoptosis in human leukemia cells through a

reactive oxygen species (ROS)-dependent mechanism

Girija Dasmahapatra, Mohamed Rahmani, Dent, and Grant*

Department of Medicine, Virginia Commonwealth University, Richmond,

VA, USA

Department of Radiation Oncology, 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.