Zileuton induces hemoglobin F synthesis in erythroid progenitors: Role of the L-arginine-nitric oxide signaling pathway

Johnson Haynes, B. Surendra Baliga, Boniface Obiako, Solomon Ofori-Acquah, Betty Pace

Research output: Contribution to journalArticle

39 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)3945-3950
Number of pages6
JournalBlood
Volume103
Issue number10
DOIs
StatePublished - May 15 2004
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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