Valproic acid, trichostatin and their combination with hemin preferentially enhance gamma-globin gene expression in human erythroid liquid cultures

Background and Objectives. In addition to conventional therapy, current tre atment of thalassemia and sickle cell anemia includes inducers of hemoglobi n F synthesis (hydroxyurea, erythropoietin, azacytidine and butyrate), Howe ver, because of concerns about the dose-limiting myelotoxicity, potential c arcinogenicity and high cost of the above agents, an intensive search for l ess toxic or more effective drugs is ongoing;. In this study we tested the effect of valproic acid and trichostatin, alone or in combination with hemi n, on gamma chain synthesis in human erythroid liquid cultures. Design and Methods. The agents were tested on erythroid human liquid cultur es derived from normal peripheral blood, peripheral blood from beta (s)/bet a (thal) patients, normal cord blood and normal bone marrow samples. The ef fect of the agents was expressed as increase of gamma/gamma+beta m-RNA, mea sured with competitive reverse transcriptase-polymerase chain recation (RT- PCR), or as increase of HbF, measured by high performance liquid chromatogr aphy (HPLC). Results. Addition of valproic acid or trichostatin to human erythroid cell cultures preferentially enhanced gamma mRNA synthesis in all blood samples (2.9 to 3.5-fold). The addition of hemin enhanced the effect up to 10-fold. Interpretation and Conclusions. Valproic acid, trichostatin and their combi nation with hemin (all three FDA-approved drugs) preferentially increase ga mma -globin chain synthesis and may be helpful for the treatment of hemoglo binopathies. (C) 2001, Ferrata Storti Foundation.