Abstract
Oxidative stress has been implicated in the development of several types of cancer, including myelodysplastic syndromes (MDS), as well as in the resistance to treatment. In this work, we assessed the potential of oxidative stress parameters to predict the response to erythropoiesis-stimulating agents (ESAs) in lower-risk MDS patients. To this end, we analyzed the systemic levels of reactive species (peroxides and NO), antioxidant defenses (uric acid, vitamin E, vitamin A, GSH, GSSG, TAS, as well as GPX and GR activities], and oxidative damage (8-OH-dG and MDA) in 66 MDS patients, from those 44 have been treated with ESA. We also calculated the peroxides/TAS and NO/TAS ratios and analyzed the gene expression of levels of the redox regulators, NFE2L2 and KEAP1. We found that patients that respond to ESA treatment showed lower levels of plasma peroxides (p < 0.001), cellular GSH (p < 0.001), and cellular GR activity (p = 0.001) when compared to patients who did not respond to ESA treatment. ESA responders also showed lower levels of peroxides/TAS ratio (p < 0.001) and higher levels of the expression of the NFE2L2 gene (p = 0.001) than those that did not respond to ESA treatment. The levels of plasmatic peroxides shown to be the most accurate biomarker of ESA response, with good sensitivity (80%) and specificity (100%) and is an independent biomarker associated with therapy response. Overall, the present study demonstrated a correlation between oxidative stress levels and the response to ESA treatment in lower-risk MDS patients, with the plasmatic peroxides levels a good predictive biomarker of drug (ESA) response.
Highlights
Myelodysplastic syndromes (MDS) are clonal hematological malignancies that comprises several subtypes with different biological and clinical presentations
We found that patients who respond to erythropoiesis-stimulating agents (ESAs) treatment have lower levels of plasma peroxides, cellular GSH, cellular glutathione reductase (GR) activity, peroxides/total antioxidant status (TAS) ratio, and higher levels of NFE2L2 gene expression in comparison to patients who did not respond to ESA treatment
To the best of our knowledge, only one study analyzed the association between oxidative stress and ESA response
Summary
Myelodysplastic syndromes (MDS) are clonal hematological malignancies that comprises several subtypes with different biological and clinical presentations. These diseases are frequently characterized by inefficient hematopoiesis, dysplasia in one or more myeloid cell lineages, variable degrees and number of cytopenias, and increased risk of progression to acute myeloid leukemia (AML) (Jhanwar, 2015; Cazzola, 2020). The peripheral cytopenias frequently observed in these patients are a consequence of the ineffective hematopoiesis and could involve all myeloid lineages (Mufti, 2004). Precursors conditions of MDS, such as clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS), has been identified (Cazzola, 2020) that allow an earlier diagnosis and could modify the MDS approach
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