Hydroxycarbamide and Sickle Cell Anemia: Paradoxical Effects Related to Redox Mechanisms of Cellular Adaptation

Sickle cell anemia (SCA) is a hemolytic anemia characterized by a chronic redox imbalance with few disease-modifying treatments available. In this study, we aimed to determine the influence of hydroxycarbamide (HC) treatment on the redox mechanisms of cellular adaptation in patients with SCA. We analyzed 10 patients treated (HC+) and 9 not treated (HC-). We evaluated, by RT-qPCR, the transcript levels of the transcription factors NRF2 and ATF4, their modulators (KEAP1, AKT, and PI3K), and the antioxidants (SOD1, CAT, PRDX1, and GPX1). We also collected data on biochemical parameters, including total leukocyte count, direct and indirect bilirubin, lactic acid dehydrogenase (LDH), and fetal hemoglobin (HbF%) levels, by analyzing the participants' medical records. Among the results obtained, NRF2 and AKT presented increased mRNA levels in the HC+ group, but reduced ATF4, CAT, and SOD1 mRNA levels. Multivariate statistical analysis ranked NRF2 and ATF4 as the markers that most characterized the groups studied. Therefore, taking together our results and the literature, we suggest that HC use results in a dynamic relationship between the redox signaling pathways of the investigated transcription factors triggered as part of an adaptive response to this medication, associated with their involvement in Hb F production.