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


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.


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.
Marianna
P
P
First Department of Medicine, University of Athens, Laikon Hospital, Greece. dloukop@otenet.gr
Kollia
P
P
Akel
S
S
Papassotiriou
Y
Y
Stamoulakatou
A
A
Loukopoulos
D
D
D000935:Antifungal Agents / Q000494:pharmacology; D002478:Cells, Cultured / Q000187:drug effects; D004347:Drug Interactions; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018682:GABA Agents / Q000494:pharmacology; D015870:Gene Expression / Q000235:genetics; D005914:Globins / Q000187:drug effects* / Q000235:genetics; D006427:Hemin / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D014635:Valproic Acid / Q000494:pharmacology*; D017086:beta-Thalassemia / Q000473:pathology
D000935:Antifungal Agents; D018682:GABA Agents; D006877:Hydroxamic Acids; C012589:trichostatin A; D014635:Valproic Acid; D006427:Hemin; D005914:Globins