Nitric Oxide Mediation in Hydroxyurea and Nitric Oxide Metabolites' Inhibition of Erythroid Progenitor Growth.

Tijana Subotički,Marijana Kovačić,Dragoslava Djikić,Juan F Santibanez,Milica Tošić,Olivera Mitrović Ajtić,Vladan P Čokić

doi:10.3390/biom11111562

Abstract

In several systems, hydroxyurea has been shown to trigger nitric oxide (NO) release or activation of NO synthase (NOS). To elucidate this duality in its pharmacological effects, during myelosuppression, we individually examined hydroxyurea’s (NO releasing agent) and NO metabolites’ (stable NO degradation products) effects on erythroid colony growth and NOS/NO levels in mice using NO scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO). Hydroxyurea and nitrite/nitrate decreased the bone marrow cellularity that was blocked by PTIO only for the NO metabolites. Hydroxyurea inhibition of colony-forming unit-erythroid (CFU-E) formation and reticulocytes was reversed by PTIO. Moreover, hydroxyurea, through a negative feedback mechanism, reduced inducible NOS (iNOS) expressing cells in CFU-E, also prevented by PTIO. Nitrate inhibition of burst-forming units-erythroid (BFU-E) colony growth was blocked by PTIO, but not in mature CFU-E. The presented results reveal that NO release and/or production mediates the hydroxyurea inhibition of mature erythroid colony growth and the frequency of iNOS immunoreactive CFU-E.

Highlights

Nitric oxide (NO) is an intracellular metabolite of hydroxyurea used as a therapeutic in sickle cell anemia [1,2]
In preclinical in vitro studies, hydroxyurea increases endothelial cell production of NO by stimulating endothelial NO synthase [3], while the later study showed that hydroxyurea enhances nitrite production only in combination with heme [4]
We proposed that hydroxyurea inhibits the frequency of constitutive isoforms of in bone marrow cells, as well as the frequency of inducible NOS (iNOS) expressing cells in colony-forming unit-erythroid (CFU-E) colonies

Summary

Introduction

Nitric oxide (NO) is an intracellular metabolite of hydroxyurea used as a therapeutic in sickle cell anemia [1,2]. Hydroxyurea regulation of erythroid cell proliferation and apoptosis is NOS dependent [5]. Hydroxyurea in vitro decreases the growth of erythroid colonies with the participation of NOS [6,7]. NO donors inhibit the growth of erythroid and myeloid colonies derived from bone marrow mononuclear and CD34+ cells [8,9]. Hydroxyurea reduction in leukocyte adhesion and extravasation is reversed by the NO scavenger, but not by NOS inhibition [10]

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Discussion

Conclusion