PT  - JOURNAL ARTICLE
AU  - FADERL, STEFAN
AU  - FERRAJOLI, ALESSANDRA
AU  - HARRIS, DAVID
AU  - VAN, QUIN
AU  - PRIEBE, WALDEMAR
AU  - ESTROV, ZEEV
TI  - WP-1034, A Novel JAK-STAT Inhibitor, with Proapoptotic and Antileukemic Activity in Acute Myeloid Leukemia (AML)
DP  - 2005 May 01
TA  - Anticancer Research
PG  - 1841--1850
VI  - 25
IP  - 3B
4099  - http://ar.iiarjournals.org/content/25/3B/1841.short
4100  - http://ar.iiarjournals.org/content/25/3B/1841.full
SO  - Anticancer Res2005 May 01; 25
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