TY - JOUR
T1 - Zileuton induces hemoglobin F synthesis in erythroid progenitors
T2 - Role of the L-arginine-nitric oxide signaling pathway
AU - Haynes, Johnson
AU - Surendra Baliga, B.
AU - Obiako, Boniface
AU - Ofori-Acquah, Solomon
AU - Pace, Betty
PY - 2004/5/15
Y1 - 2004/5/15
N2 - 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 analog of hydroxyurea, possessed Hb F-inducing properties and the potential role nitric oxide plays. ZL caused a dose-dependent increase in γ-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-PCPT-cGMP (8-(4-chlorophenylthio)guanosine 3′, 5′-cyclic monophosphate) 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 nor L-arginine 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.
AB - 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 analog of hydroxyurea, possessed Hb F-inducing properties and the potential role nitric oxide plays. ZL caused a dose-dependent increase in γ-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-PCPT-cGMP (8-(4-chlorophenylthio)guanosine 3′, 5′-cyclic monophosphate) 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 nor L-arginine 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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U2 - 10.1182/blood-2003-08-2969
DO - 10.1182/blood-2003-08-2969
M3 - Article
C2 - 14764535
AN - SCOPUS:2342455050
SN - 0006-4971
VL - 103
SP - 3945
EP - 3950
JO - Blood
JF - Blood
IS - 10
ER -