Retrospective analysis of long-term toxicity of Hydroxyurea in patients with sickle cell anemia

• Grant number: 24/06454-8
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Effective date (Start): May 01, 2024
• Effective date (End): April 30, 2025
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Fernando Ferreira Costa
• Grantee: Mabel Rodrigues Rios
• Host Institution: Centro de Hematologia e Hemoterapia (HEMOCENTRO). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 19/18886-1 - Pathophysiological mechanisms and treatment of red blood cell abnormalities, AP.TEM

Abstract

Sickle cell diseases (SCDs) are a group of inherited disorders characterized by mutations in the gene encoding the beta subunit (HBB) of hemoglobin, leading to the formation of abnormal hemoglobin (hemoglobin S, HbS). Sickle cell disease occurs when there is homozygosity for HbS or double heterozygosity with another abnormal hemoglobin, such as Hb²0, Hb²+, HbD, and HbC. The sickling of erythrocytes occurs due to the polymerization of HbS within the cell under conditions of deoxygenation, leading to a process of hemolysis, endothelial activation, inflammatory process through the interaction between erythrocytes and leukocytes and platelets, and activation of coagulation pathways. As a consequence, there is a chronic state of ischemia-reperfusion and oxidative stress.The clinical consequences of SCDs involve both acute conditions such as painful crises, acute chest syndrome, priapism, ischemic events in the central nervous system, hepatic and splenic sequestration, avascular necrosis of long bones, and worsening of anemia, as well as chronic complications in target organs, including cardiac hypertrophy, pulmonary artery hypertension, chronic pain, renal injury, osteoporosis, erectile dysfunction, retinopathy, hepatopathy, cholelithiasis, cognitive dysfunction, and cutaneous ulcers, among others.Currently, the goal of SCD treatment is to reduce sickling crises and their chronic complications. In this regard, hydroxyurea (HU) has been shown to be a drug capable of modifying the natural history of the disease, benefiting in reducing crises and long-term complications in SCDs, and has been used widely at increasingly early ages. In SCDs, HU induces the expression of fetal hemoglobin (HbF), which, in turn, inhibits the polymerization of HbS, decreasing cellular rigidity and hemolysis, improving anemia. It also modulates nitric oxide, a potent vasodilator, decreases erythrocyte adhesion, and the number of leukocytes.The mechanism of action of HU involves the inhibition of ribonucleotide reductase activity by interrupting the transfer of electrons coupled to protons that catalyze the production of new deoxyribonucleotides (dNTPs). HU activity is most prominent in the S phase of the cell cycle and prevents DNA synthesis, causing cell cycle arrest and activation of the checkpoint that delays mitosis and interrupts cell cycle progression until DNA replication is completed and any DNA damage is corrected. This checkpoint activation is crucial for proper cell proliferation and is carefully regulated by signaling kinases. It is not yet known how kinases precisely identify DNA damage sites.In vitro, high concentrations of HU or long incubation periods can cause serious damage to DNA strands, leading to a variety of dysfunctions such as accumulation of damaged DNA sites (which later result in chromosomal damage) and generation of reactive oxygen species, which induce cytokinesis arrest due to oxidative stress and contribute to HU genotoxicity.Clinically, there are no large-scale studies evaluating the long-term toxicity of HU in SCD patients. Considering its widespread and increasingly early use, it is crucial that new studies assess potential medication toxic effects in this population.