RT Journal Article
SR Electronic
T1 The Organic Arsenic Derivative GMZ27 Induces PML–RARα-Independent Apoptosis in Myeloid Leukemia Cells
JF Anticancer Research
JO Anticancer Res
FD International Institute of Anticancer Research
SP 2871
OP 2880
VO 32
IS 7
A1 XIAODONG CHENG
A1 ALFONSO QUINTÁS-CARDAMA
A1 MIRNA GOLEMOVIC
A1 RALPH ZINGARO
A1 MING-ZHANG GAO
A1 EMIL J. FREIREICH
A1 MICHAEL ANDREEFF
A1 HAGOP M. KANTARJIAN
A1 SRDAN VERSTOVSEK
YR 2012
UL http://ar.iiarjournals.org/content/32/7/2871.abstract
AB Arsenic trioxide (ATO) is an inorganic arsenic derivative that is very effective against acute promyelocytic leukemia. However, organic arsenic derivatives (OAD) have a more favorable toxicity profile than ATO. We herein characterized dipropil-S-glycerol arsenic (GMZ27), a novel OAD. GMZ27 had potent antiproliferative activity against human acute myeloid leukemia (AML) cell lines that was higher than that of ATO. In contrast to ATO, GMZ27 only marginally induced maturation of leukemia cells and had no effect on the cell cycle. The anti-leukemia activity of GMZ27 against AML cells was independent of the presence of the PML–RARα fusion protein. GMZ27 dissipates mitochondrial transmembrane potential, and induces cleavage of caspase 9 and activation of caspase 3 without altering the expression levels of (BCL-2), BAX and BCL-xl. GMZ27 induces the formation of intracellular superoxide, a reactive oxygen species (ROS) which plays a major role in the antileukemia activity of this OAD. In addition to ROS generation, GMZ27 concomitantly reduces intracellular glutathione which markedly weakens the cellular antioxidant capacity, thus enhancing the detrimental intracellular effects of ROS production. These results indicate that GMZ27 induces apoptosis in AML cells in a PML–RARα-independent fashion, through the induction of ROS production. This activity provides the rationale for the testing of GMZ27 in patients with AML.