Τίτλος:
Compounds of the anthracycline family of antibiotics elevate human
gamma-globin expression both in erythroid cultures and in a transgenic
mouse model
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
We examined the effect of the anthracyclines aclarubicin, bleomycin,
daunorubicin, doxorubicin and idarubicin on human gamma- and beta-globin
promoter activity in an in vitro luciferase assay, ex vivo in erythroid
cultures and in vivo in transgenic mice carrying the human gamma-globin
gene. Effects in erythroid liquid cultures derived from healthy donors
were assayed by evaluating HbF production with high performance liquid
chromatography and by measuring mRNA levels of the globin genes and the
proportion of erythroblasts containing HbF. Compounds testing positive
in the in vitro and ex vivo assays were applied to erythroid cultures
derived from thalassaemic patients. Doxorubicin, idarubicin and
daunorubicin increased HbF production in cultures of both, healthy and
thalassaemic donors. Daunorubicin induced HbF in thalassaemic cells ex
vivo with the highest statistical significance and, importantly and in
contrast to the clinical HbF inducer hydroxyurea, showed specific
induction of gamma-globin without associated induction of alpha-globin.
Daunorubicin was screened in transgenic mice carrying the human
(A)gamma-globin gene, and it resulted in increased (A)gamma-globin mRNA
levels. Our results indicate that anthracyclines are a promising group
of compounds with the potential to provide lead substances for the
synthesis of new agents with clinical applications as gamma-globin gene
inducers. In parallel, future studies of the epigenetic effects of the
five anthracyclines on the beta-globin locus will generate possible
mechanistic leads on the regulation of the globin genes. (C) 2009
Elsevier Inc. All rights reserved.
Συγγραφείς:
Spyrou, Pandelis
Phylactides, Marios
Lederer, Carsten W. and
Kithreotis, Lucas
Kirri, Andriani
Christou, Soteroulla and
Kkolou, Elena
Kanavakis, Emanuel
Anagnou, Nicholas P. and
Stamatoyannopoulos, George
Kleanthous, Marina
Περιοδικό:
BLOOD CELLS MOLECULES AND DISEASES
Εκδότης:
ACADEMIC PRESS INC ELSEVIER SCIENCE
Λέξεις-κλειδιά:
Anthracycline; fetal haemoglobin; MEL cells; BFU-E; Beta-thalassaemia
DOI:
10.1016/j.bcmd.2009.10.008
