BACKGROUND AND OBJECTIVES: In addition to conventional therapy, current treatment of thalassemia and sickle cell anemia includes inducers of hemoglobin F synthesis (hydroxyurea, erythropoietin, azacytidine and butyrate). However, because of concerns about the dose-limiting myelotoxicity, potential carcinogenicity and high cost of the above agents, an intensive search for less toxic or more effective drugs is ongoing. In this study we tested the effect of valproic acid and trichostatin, alone or in combination with hemin, on gamma chain synthesis in human erythroid liquid cultures. DESIGN AND METHODS: The agents were tested on erythroid human liquid cultures derived from normal peripheral blood, peripheral blood from beta(s)/beta(thal) patients, normal cord blood and normal bone marrow samples. The effect of the agents was expressed as increase of gamma/gamma+beta m-RNA, measured with competitive reverse transcriptase-polymerase chain recation (RT-PCR), or as increase of HbF, measured by high performance liquid chromatography (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 combination with hemin (all three FDA-approved drugs) preferentially increase gamma-globin chain synthesis and may be helpful for the treatment of hemoglobinopathies.
BACKGROUND AND OBJECTIVES: In addition to conventional therapy, current treatment of thalassemia and sickle cell anemia includes inducers of hemoglobin F synthesis (hydroxyurea, erythropoietin, azacytidine and butyrate). However, because of concerns about the dose-limiting myelotoxicity, potential carcinogenicity and high cost of the above agents, an intensive search for less toxic or more effective drugs is ongoing. In this study we tested the effect of valproic acid and trichostatin, alone or in combination with hemin, on gamma chain synthesis in human erythroid liquid cultures. DESIGN AND METHODS: The agents were tested on erythroid human liquid cultures derived from normal peripheral blood, peripheral blood from beta(s)/beta(thal) patients, normal cord blood and normal bone marrow samples. The effect of the agents was expressed as increase of gamma/gamma+beta m-RNA, measured with competitive reverse transcriptase-polymerase chain recation (RT-PCR), or as increase of HbF, measured by high performance liquid chromatography (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 combination with hemin (all three FDA-approved drugs) preferentially increase gamma-globin chain synthesis and may be helpful for the treatment of hemoglobinopathies.
Authors: James E Bradner; Raymond Mak; Shyam K Tanguturi; Ralph Mazitschek; Stephen J Haggarty; Kenneth Ross; Cindy Y Chang; Jocelyn Bosco; Nathan West; Elizabeth Morse; Katherine Lin; John Paul Shen; Nicholas P Kwiatkowski; Nele Gheldof; Job Dekker; Daniel J DeAngelo; Steven A Carr; Stuart L Schreiber; Todd R Golub; Benjamin L Ebert Journal: Proc Natl Acad Sci U S A Date: 2010-06-28 Impact factor: 11.205
Authors: Ali Dehghani Fard; Seyed Ahmad Hosseini; Mohammad Shahjahani; Fatemeh Salari; Kaveh Jaseb Journal: Int J Hematol Oncol Stem Cell Res Date: 2013