Hematology Center, School of Medical Sciences, University of Campinas (UNICAMP), Brazil (W.A.F., H.C., C.L., C.B.A., P.L.B., E.M.F.G., L.T., L.I.M., C.F.F.-P., F.C.L., F.G., S.S.T.O., F.F.C., N.C.); Bayer AG, Pharmaceuticals - Drug Discovery, Wuppertal, Germany (D.B., J.P.S., P.S.); Ruth L. and David S Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York (P.S.F.); and Hannover Medical School, Institute of Pharmacology, Hannover, Germany (P.S.).
Hematology Center, School of Medical Sciences, University of Campinas (UNICAMP), Brazil (W.A.F., H.C., C.L., C.B.A., P.L.B., E.M.F.G., L.T., L.I.M., C.F.F.-P., F.C.L., F.G., S.S.T.O., F.F.C., N.C.); Bayer AG, Pharmaceuticals - Drug Discovery, Wuppertal, Germany (D.B., J.P.S., P.S.); Ruth L. and David S Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York (P.S.F.); and Hannover Medical School, Institute of Pharmacology, Hannover, Germany (P.S.)
J Pharmacol Exp Ther. 2020 Sep;374(3):469-478. doi: 10.1124/jpet.119.264606. Epub 2020 Jul 6.
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 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 -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 STATEMENT: This 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.
镰状细胞贫血症（SCA）的复杂病理生理学涉及血管内溶血性过程和反复的血管阻塞，由慢性血管炎症驱动，导致该疾病的严重临床并发症，包括反复发生疼痛性血管阻塞发作。羟基脲是唯一常用于 SCA 治疗的药物，是一种细胞抑制剂，但它似乎具有一氧化氮/可溶性鸟苷酸环化酶（sGC）调节活性。为了寻找可以进一步降低 SCA 血管阻塞发作频率的新型药物，以补充或替代羟基脲的使用，我们研究了 sGC 激动剂 BAY 60-2770（sGC 激活剂）和 BAY 41-2272（sGC 刺激剂）在存在或不存在羟基脲的情况下对 SCA 血管阻塞机制和细胞募集的影响，无论是在体外还是体内。这些药物显著降低了体外刺激的人类 SCA 中性粒细胞的粘附特性，同时抑制了表面 2-整合素的激活。单次给予 BAY 60-2770 或 BAY 41-2272 可减少 SCA 血管阻塞小鼠模型中肿瘤坏死因子细胞因子诱导的白细胞募集。重要的是，两种激动剂的体内作用都因羟基脲的共同给药而显著增强。红细胞胎儿血红蛋白（HbF）升高也是 SCA 治疗的主要目标。在培养的红白血病细胞中，BAY 41-2272 但不是浓度为 BAY 60-2770 显著诱导 -球蛋白基因转录并与 HbF 产生相关。总之，sGC 激动剂药物可能是治疗 SCA 的一种有前途的方法，可单独使用或与羟基脲联合使用。意义声明：这项临床前研究表明，sGC 激动剂和激活剂是抑制人类和镰状细胞贫血症（SCA）小鼠白细胞粘附和募集的有效抑制剂，可能是减少 SCA 血管阻塞发作频率的有前途的方法。羟基脲是一种常用于治疗 SCA 的药物，在体内研究中发现它增强了 sGC 激动剂的有益作用，这意味着这些类化合物可以单独使用或联合使用。
