Abstract

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 β2-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.SIGNIFICANCE STATEMENTThis preclinical study demonstrates that stimulators and activators of sGC are potent inhibitors of the adhesion and recruitment of leukocytes from humans and in mice with sickle cell anemia (SCA) and may represent a promising approach for diminishing vaso-occlusive episode frequency in SCA. Hydroxyurea, a drug already frequently used for treating SCA, was found to potentiate the beneficial effects of sGC agonists in in vivo studies, implying that these classes of compounds could be used alone or in combination therapy.

Highlights

  • As gene expression of both soluble guanylyl cyclase (sGC) subunits was confirmed in these cells, albeit at lower levels than those observed in CD34+ hematopoietic stem cells, we looked at how sGC agonism may modulate neutrophil adhesive properties

  • Sickle cell anemia is recognized as a global health problem (Kato et al, 2018), and curative therapy for sickle cell anemia (SCA) exists in the form of hematopoietic stem cell transplantation, its availability is very restricted (Yawn et al, 2014)

  • Despite concerted efforts by researchers and the pharmaceutical industry to develop novel drugs for the treatment of SCA (Telen, 2016; Conran and Torres, 2019), only three substances have been approved by the Food and Drug Administration for SCA therapy since hydroxyurea’s approval over 20 years ago, and it is probable that multidrug approaches, possibly still involving the use of hydroxyurea, will evolve for the management of the disease (Carden and Little, 2019)

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Summary

Introduction

W.A.F. received a postdoctoral fellowship grant from Bayer Pharma AG. H.C., F.G., L.T., E.M.F.G., P.L.B., and L.I.M. are recipients of fellowships from Fundação de Amparo à Pesquisa do Estado de S. W.A.F. received a postdoctoral fellowship from Bayer AG Pharmaceuticals. J.P.S. is senior advisor of Bayer AG. D.B. and P.S. are full-time employees of Bayer AG Pharmaceuticals

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