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Hydroxyurea is a newly approved therapeutic agent for the treatment of sickle-cell disease. Hydroxyurea reduces the number of painful crises in sickle-cell patients presumably by increasing the levels of fetal hemoglobin, which has a large solubilizing effect on sickle-cell hemoglobin and reduces polymerization (1). Despite being used to treat a number of cancers for nearly 30 years, the mechanism of how hydroxyurea increases fetal hemoglobin levels remains unclear. In this issue of the JCI, Cokic et al. present results that provide the first explanation of how hydroxyurea increases fetal hemoglobin levels (2). Specifically, they show that fetal hemoglobin increases in response to activation of soluble guanylyl cyclase (sGC) by hydroxyurea-derived NO. The importance of this work manifests itself in at least three ways: 1) the in vitro identification of some of the molecular species involved in fetal hemoglobin induction, 2) a further demonstration of a role for NO in the activity of hydroxyurea, and 3) the application of this work to the development of new NO based treatments for sickle-cell disease.  The work described in this study (2) relies on the authors’ ability to recognize clues from previous basic and clinical research. First, hydroxyurea reacts with enzymes and proteins, particularly heme-containing proteins, to release NO (3–7). Other studies reveal that patients taking hydroxyurea demonstrate increased levels of nitrite, nitrate, and iron nitrosyl hemoglobin, all of which are markers for NO (8–10). Finally, sGC activators increase γ-globin gene expression in both eryth-roleukemic cells and primary human erythroblasts and sGC inhibitors prevent this increase (11). The combination of these results with the ability of NO to stimulate sGC led to the design and execution of the described experiment to determine the effect of nitric oxide donors and hydroxyurea on fetal hemoglobin induction.

A role for nitric oxide in hydroxyurea-mediated fetal hemoglobin induction