RT Journal Article
SR Electronic
T1 WP-1034, A Novel JAK-STAT Inhibitor, with Proapoptotic and Antileukemic Activity in Acute Myeloid Leukemia (AML)
JF Anticancer Research
JO Anticancer Res
FD International Institute of Anticancer Research
SP 1841
OP 1850
VO 25
IS 3B
A1 STEFAN FADERL
A1 ALESSANDRA FERRAJOLI
A1 DAVID HARRIS
A1 QUIN VAN
A1 WALDEMAR PRIEBE
A1 ZEEV ESTROV
YR 2005
UL http://ar.iiarjournals.org/content/25/3B/1841.abstract
AB Cytokine stimulation induces proliferation and growth of acute myeloid leukemia (AML) blasts and high levels of cytokines have been associated with poor prognosis in AML. The Jak-Stat pathway constitutes a major mediator of cytokine activity. We investigated whether WP-1034, a novel Jak-Stat inhibitor, is active against AML blasts. OCIM2 and fresh AML cells were incubated with 1 to 6 μM WP-1034 to determine its effect on proliferation. WP-1034 effectively inhibited proliferation of OCIM2 cells and fresh AML samples. We then analyzed the expressions of Stat 1, 3, and 5, as well as Phospho-Stat 1, 3, and 5 by Western immunoblotting after incubation of OCIM2 cells without and with 1 to 10 μM WP-1034 for 2 hours, and at 5 μM from 20 minutes up to 4 hours and found that WP-1034 blocked Stat 3 and 5 activation. Analysis of cell cycle status by PI staining and flow cytometry showed that WP-1034 caused cell cycle arrest of OCIM2 cells in sub-G0 phase. We then evaluated the induction of apoptosis of OCIM2 cells following incubation with WP-1034 at 3 to 6 μM by annexin V-CY5 assay and analyzed caspase 3 and PARP cleavage using Western immunoblotting. We found that WP-1034 induced apoptosis of OCIM2 cells and that induction of apoptosis involved cleavage of caspase 3 and the DNA repair enzyme poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP). Taken together, our data suggest that WP-1034 is a potent inhibitor of AML cell proliferation by inhibition of Stat 3 and 5 and induction of caspase-dependent apoptosis. Copyright© 2005 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved