Compounds of the anthracycline family of antibiotics elevate human gamma-globin expression both in erythroid cultures and in a transgenic mouse model.
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.
Spyrou
Pandelis
P
Molecular Genetics Thalassaemia Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus. pandelis@cing.ac.cy
Phylactides
Marios
M
Lederer
Carsten W
CW
Kithreotis
Lucas
L
Kirri
Andriani
A
Christou
Soteroulla
S
Kkolou
Elena
E
Kanavakis
Emanuel
E
Anagnou
Nicholas P
NP
Stamatoyannopoulos
George
G
Kleanthous
Marina
M
D000818:Animals; D018943:Anthracyclines / Q000008:administration & dosage / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D041905:Erythroid Cells / Q000187:drug effects; D005319:Fetal Hemoglobin / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D013789:Thalassemia / Q000188:drug therapy / Q000235:genetics; D055544:beta-Globins / Q000235:genetics; D055545:gamma-Globins / Q000235:genetics*
D018943:Anthracyclines; D000900:Anti-Bacterial Agents; D012333:RNA, Messenger; D055544:beta-Globins; D055545:gamma-Globins; D005319:Fetal Hemoglobin