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Blood, 15 May 2004, Vol. 103, No. 10, pp. 3945-3950.
Prepublished online as a Blood First Edition Paper on February 5, 2004; DOI 10.1182/blood-2003-08-2969.
Submitted September 2, 2003
Accepted January 23, 2004
Zileuton Induces Hemoglobin F Synthesis in Erythroid Progenitors: Role of the L-Arginine-Nitric Oxide Signaling Pathway
Johnson Haynes*, B S Baliga, Boniface Obiako, Solomon Ofori-Acquah, and Betty Pace
Medicine, University of South Alabama, Mobile, AL, USA
Pediatrics, University of South Alabama, Mobile, AL, USA
Cell Biology and Neuroscience, University of South Alabama, Mobile, AL, USA
Molecular and Cell Biology, University of Texas at Dallas, Richardson, TX, USA
* Corresponding author; email: jhaynes{at}usouthal.edu.
Induction of fetal hemoglobin (Hb F) is an important therapeutic tool in ameliorating complications of sickle cell disease. Nitric oxide has been implicated in the mechanism of Hb F synthesis induced by hydroxyurea (HU). This study examined whether zileuton (ZL), a structural analogue of hydroxyurea, possessed Hb F inducing properties and the potential role nitric oxide plays. ZL caused a dose-dependent increase in Abstract
Induction of fetal hemoglobin (Hb F) is an important therapeutic tool in ameliorating complications of sickle cell disease. Nitric oxide has been implicated in the mechanism of Hb F synthesis induced by hydroxyurea (HU). This study examined whether zileuton (ZL), a structural analogue of hydroxyurea, possessed Hb F inducing properties and the potential role nitric oxide plays. ZL caused a dose-dependent increase in  -globin expression in K562 cells. This effect was confirmed by a dose-dependent increase in Hb F synthesis in erythroid progenitors from individuals with sickle cell anemia and normal hemoglobin genotypes. L-arginine had no effect on Hb F production; however, it dose-dependently inhibited ZL's ability to induce Hb F. The nitric oxide synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA), inhibited L-arginine's effect and restored ZL-mediated increase in Hb F synthesis. In addition, 8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphate (8-PCPT-cGMP), inhibited ZL-mediated induction of Hb F synthesis. When comparing L-NMMA effects alone on ZL and HU, a partial reversal of increased Hb F synthesis was seen only with HU. Neither L-arginine alone or in combination with L-NMMA effected hydroxyurea-mediated induction of Hb F synthesis.This study demonstrates that ZL induces Hb F through a mechanism that involves L-arginine/nitric oxide/cGMP in a manner distinctly different from HU.
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