title: The investigation of resveratrol and analogs as potential inducers of fetal hemoglobin.
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.
authors.affiliation: Cyprus Institute of Neurology and Genetics, Molecular Genetics Thalassaemia Dept, Nicosia, Cyprus; King's College London, Faculty of Life Sciences & Medicine, London, United Kingdom.
authors.forename: Andria
authors.initials: A
authors.lastname: Theodorou
authors.affiliation: Cyprus Institute of Neurology and Genetics, Molecular Genetics Thalassaemia Dept, Nicosia, Cyprus. Electronic address: mphylact@cing.ac.cy.
authors.forename: Marios
authors.initials: M
authors.lastname: Phylactides
authors.affiliation: University of Modena and Reggio Emilia, Department of Life Sciences, Regio Emilia, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Forti
authors.affiliation: University of Modena and Reggio Emilia, Department of Life Sciences, Regio Emilia, Italy.
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Cramarossa
authors.affiliation: Cyprus Institute of Neurology and Genetics, Molecular Genetics Thalassaemia Dept, Nicosia, Cyprus.
authors.forename: Pantelis
authors.initials: P
authors.lastname: Spyrou
authors.affiliation: University of Ferrara, Dept of Biochemistry and Molecular Biology, Ferrara, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Gambari
authors.affiliation: King's College London, Faculty of Life Sciences & Medicine, London, United Kingdom; The National Institute of Health, National Lung and Blood Institute, Sickle Cell Branch, Bethesda, USA.
authors.forename: Swee Lay
authors.initials: SL
authors.lastname: Thein
authors.affiliation: Cyprus Institute of Neurology and Genetics, Molecular Genetics Thalassaemia Dept, Nicosia, Cyprus.
authors.forename: Marina
authors.initials: M
authors.lastname: Kleanthous
mesh_terms: D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000187:drug effects; D005319:Fetal Hemoglobin / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D013267:Stilbenes; D005319:Fetal Hemoglobin; D000077185:Resveratrol
keywords: Antioxidant; Beta-thalassemia; Fetal hemoglobin; Globin; Resveratrol