Beneficial Effects of Soluble Guanylyl Cyclase Stimulation and Activation in Sickle Cell Disease Are Amplified by Hydroxyurea: In Vitro and In Vivo Studies

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 374; no. 3; pp. 469 - 478
• Main Authors: Ferreira, W.A., Chweih, H., Lanaro, C., Almeida, C.B., Brito, P.L., Gotardo, E.M.F., Torres, L., Miguel, L.I., Franco-Penteado, C.F., Leonardo, F.C., Garcia, F., Saad, S.T.O., Frenette, P.S., Brockschnieder, D., Costa, F.F., Stasch, J.P., Sandner, P., Conran, N.
• Format: Journal Article
• Language: English
• Published: Bethesda, MD The American Society for Pharmacology and Experimental Therapeutics 01-09-2020
• Subjects: Drug Discovery and Translational Medicine
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.119.264606

The complex pathophysiology of sickle cell anemia (SCA) involves intravascular hemolytic processes and recurrent vaso-occlusion, driven by chronic vascular inflammation, which result in the disease’s severe clinical complications, including recurrent painful vaso-occlusive episodes. Hydroxyurea, the only drug frequently used for SCA therapy, is a cytostatic agent, although it appears to exert nitric oxide/soluble guanylyl cyclase (sGC) modulating activity. As new drugs that can complement or replace the use of hydroxyurea are sought to further reduce vaso-occlusive episode frequency in SCA, we investigated the effects of the sGC agonists BAY 60-2770 (sGC activator) and BAY 41-2272 (sGC stimulator) in the presence or absence of hydroxyurea on SCA vaso-occlusive mechanisms and cell recruitment both ex vivo and in vivo. These agents significantly reduced stimulated human SCA neutrophil adhesive properties ex vivo in association with the inhibition of surface
β
2-integrin activation. A single administration of BAY 60-2770 or BAY 41-2272 decreased tumor necrosis factor cytokine–induced leukocyte recruitment in a mouse model of SCA vaso-occlusion. Importantly, the in vivo actions of both agonists were significantly potentiated by the coadministration of hydroxyurea. Erythroid cell fetal hemoglobin (HbF) elevation is also a major goal for SCA therapy. BAY 41-2272 but not BAY 60-2770 at the concentrations employed significantly induced
γ
-globin gene transcription in association with HbF production in cultured erythroleukemic cells. In conclusion, sGC agonist drugs could represent a promising approach as therapy for SCA, for use either as stand-alone treatments or in combination with hydroxyurea.