Novel deferiprone resveratrol hybrid exhibits iron chelation and fetal hemoglobin induction in K562 cells supported by validated LC-MS/MS quantification

Multiple blood transfusions aim to improve anemia and maintain hemoglobin level in β-thalassemia patients; nonetheless, the consequent iron overloading raises serious complications. Nowadays, fetal hemoglobin (HbF) induction and iron chelation therapy are two strategic treatments for β-thalassemia aimed at ameliorating ineffective erythropoiesis and reducing complications from iron overload. Deferiprone-resveratrol hybrid (DFP-RVT) is a novel multi-target directed ligand (MTDL) which is chemically synthesized by combining DFP with RVT. According to previous reports, the DFP exhibits iron-chelating effects, while the RVT shows HbF-inducing and antioxidant properties. This study aims to investigate the effect of DFP-RVT hybrid on iron reduction and HbF production in iron-overloaded erythroleukemia (K562) cells. Results showed that treatment with a non-toxic dose of DFP-RVT led to a significant reduction in intracellular iron content and ROS levels in iron-overloaded cells. The 25 µM DFP-RVT (DFP 10.23 µM and RVT 14.77 µM equivalent) induced HbF production, represented by the increase in % F-cell and γ-globin expression compared to iron loading control. We expect that DFP-RVT will be a safe and effective HbF inducer with iron chelating property in β-thalassemia patients with iron overload. Moreover, we developed and validated an LC-MS/MS method for quantification of DFP-RVT in plasma, providing a robust tool to support its further preclinical evaluation.