Abstract
Βeta-thalassemia, is a hemoglobinopathy characterized by reduced beta-globin chain synthesis, leading to imbalanced globin chain production, ineffective erythropoiesis and anemia. Increasing gamma-globin gene expression is a promising therapeutic approach as it reduces this imbalance by combining with the excess alpha globin chains and producing fetal hemoglobin (HbF). Furthermore, increased iron absorption and repeated blood transfusions lead to iron overload and tissue damage secondary to reactive oxygen species. Compounds exhibiting both antioxidant and HbF inducing activities are, therefore, highly desirable therapeutic agents. Resveratrol, a natural phytoalexin, combines these two activities but is also cytotoxic. Nine hydroxystilbenic resveratrol derivatives were synthesized in an attempt to identify compounds that retain the HbF-inducing and antioxidant activities of resveratrol but exhibit reduced cytotoxicity. Three derivatives (P1, P4 and P11) exhibited similar hemoglobin-inducing properties to resveratrol in K562 cells, however, only P11 showed reduced cytotoxicity. All three derivatives demonstrated variable HbF-inducing activity in primary erythroid progenitor cells from healthy donors. Resveratrol and P11 increased HbF induction significantly, with P11 having the highest activity. Additionally, P4 significantly increased progenitor numbers. A combinatorial treatment in K562 cells using resveratrol and decitabine resulted in a statistically significant increase in hemoglobin-inducing activity only above the level shown by resveratrol alone.
Highlights
Βeta-thalassemia, a global health burden, is an inherited disorder of beta globin chain production
Screening of the agent in K562 cells showed resveratrol to be a highly active Hb-inducing agent resulting in a 5.7-fold increase in the number of hemoglobin containing cells and 50% cell survival relative to the untreated sample when used at 5 μM (Table 1)
This was higher than the average effect observed with 150 μM hydroxyurea [39], the positive control compound which showed an average of 4.78-fold increase in the number of Hb-positive cells at a concentration 30-fold higher than resveratrol (Table 1)
Summary
Βeta-thalassemia, a global health burden, is an inherited disorder of beta globin chain production. The disease is characterized by reduced synthesis of functional β-globin chains, leading to imbalanced globin chain ratio, ineffective erythropoiesis and anemia [1]. Thalassaemic patients require regular blood transfusions with regular iron chelation therapy as a means of managing the disease. This treatment is not curative and still has substantial morbidity. A very promising therapeutic approach for β-thalassemia is the production of fetal hemoglobin (HbF) through pharmacological reactivation of endogenous gamma-globin genes as γ-globin can substitute for the absent or reduced adult β-globin [2,3]. The currently available HbFinducing chemical agents have limited clinical application due to their moderate therapeutic properties and potential cytotoxic effects [4,5]
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