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

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.

Exploring Pharmacogenetic Factors Influencing Hydroxyurea Response in Tanzanian Sickle Cell Disease Patients: A Genomic Medicine Approach

“…Similarly, as stipulated earlier, the other two loci ( NOS1 and ARG 2) are associated with hydroxyurea metabolism. NOS1 is known to contribute to the conversion of hydroxyurea to its active form, which involves the release of nitric oxide [63] while Arginase 2 ( ARG2 ) catalyzes the conversion of arginine, the substrate for nitric oxide synthase (NOS). Our findings are well in line with this evidence and supported by a similar trend observed for both NOS1 and ARG2 which are metabolically related.…”

Acute kidney injury in Jamaicans with sickle cell disease hospitalized with COVID‐19 infection

“…Hydroxyurea use has been associated with less severe COVID infection and reduced risk of mortality in hospitalized persons with SCD. Plausible mechanisms include hydroxyurea's effect on reducing pro‐inflammatory cytokines inclusive of interleukin‐6 (IL‐6), IL‐8 and tumor necrosis factor‐alpha (TNF‐α) and beneficial effect on the microvascular circulation though increasing nitric oxide donation and intracellular signaling in SCD [ 40 , 41 ]. Although hydroxyurea is subsidized for persons with SCD since 2015 in Jamaica, its reported use is still infrequent.…”