Resveratrol, a natural antioxidant phytoalexin, and 4 synthetic derivatives can promote expression of gamma-globin gene in vitro

Resveratrol (3,4′5-trihydroxystilbene) is a naturally occurring phenolic compound. It is found in the skin of red grapes and in a variety of medicinal plants. Resveratrol presents many biological activities that have been applied against cardiovascular disease and cancer. One of Resveratrol properties is inhibition of the enzyme Ribonucleotide reductase. It has been found that some other Ribonucleotide reductase inhibitors like Hydroxyurea, Didox and Trimidox are also inducers of gammaglobin gene expression. In this study we investigated whether Resveratrol and 10 newly synthesized derivatives can act as inducers of gamma-globin gene and increase HbF levels. These derivatives were synthesized by the group of Dr. L.A Stivala (Department of Chemistry, University of Modena) by modifications of the polar groups of Resveratrol structure in an effort to increase its antioxidant activity. We examined the effect of Resveratrol and 10 of its derivatives on gamma- and beta-globin gene promoter activity in a dual luciferase assay in GM979 cells. Hydroxyurea, a known Ribonucleotide reductase inhibitor and HbF inducer and propionic acid, an HbF inducer, were used as positive control substances. The results showed that Resveratrol and 4 of its derivatives increased the gamma-globin gene promoter activity more than 3 fold. The compounds which exhibited an effect were subsequently tested in human erythroid liquid cultures derived from normal individuals and thalassemic patients. HbF content was measured by HPLC. Despite their promising effects on gamma-globin gene promoter activity in MEL cells, Resveratrol and its 4 active derivative compounds did not cause significant increase in HbF production in erythroid progenitor cells (BFUe).