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Selective toxicity of dihydroartemisinin on human CD34+ erythroid cell differentiation.

Finaurini, Sara, Ronzoni, Luisa, Colancecco, Alessandra, Cattaneo, Alessandra, Cappellini, Maria Domenica, Ward, Stephen ORCID: https://orcid.org/0000-0003-2331-3192 and Taramelli, Donatella (2010) 'Selective toxicity of dihydroartemisinin on human CD34+ erythroid cell differentiation.'. Toxicology, Vol 276, Issue 2, pp. 128-34.

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Abstract

Artemisinins are safely used in the combination therapy for uncomplicated malaria, but their employment during pregnancy is still controversial. In fact, animal studies reported that the active metabolite, dihydroartemisinin (DHA), causes embryonic erythrocytes depletion, when the treatment is performed during a critical period of time. The present study investigates the effect of DHA on human developmental erythropoiesis in order to characterize the target erythroid stage and to predict the window of susceptibility in human pregnancy. As a model for human developmental erythropoiesis, peripheral blood purified, CD34+ cells were committed towards erythrocytes and DHA (0.5 or 2 μM) was added to different erythroid stages during 14 days culture. Erythroid differentiation was investigated by cytofluorimetric analysis of Glycophorin A expression, by morphological analysis and erythroid globin gene expression analysis with real-time PCR. It was found that the effect of DHA was dependent on the maturation stage of erythroid cells. In fact when DHA was added to the pro- and basophilic erythroblasts caused a significant dose-dependent inhibition of cell proliferation and a significant delay of erythroid differentiation, as measured by morphological analysis, expression of Glycophorin A by immunofluorescence and of erythroid globin genes by real-time PCR. In contrast, the inhibition of stem cells and of early progenitors was transient and masked by the subsequent exponential cell growth. No effect was observed on mature erythroid stages. This is the first demonstration that DHA affects human erythropoiesis in vitro, in a dose- and time-dependent manner; the target population seems to be the pro-erythroblast and basophilic erythroblast stage, suggesting that DHA toxicity is limited to primitive human erythropoiesis. These findings outline the relevance of DHA dosage and timing to prevent embryotoxicity and support current WHO recommendations of avoiding malaria treatment with artemisinins during the first trimester of pregnancy.

Item Type: Article
Uncontrolled Keywords: Dihydroartemisinin; CD34+ erythroid cell differentiation; Malaria in pregnancy; Erythro-toxicity; Embryotoxicity
Subjects: QU Biochemistry > Cells and Genetics > QU 375 Cell physiology
QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 256 Antimalarials
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 770 Therapy
WQ Obstetrics > Pregnancy Complications > WQ 256 Infectious diseases
Faculty: Department: Groups (2002 - 2012) > Molecular & Biochemical Parasitology Group
Digital Object Identifer (DOI): https://doi.org/10.1016/j.tox.2010.07.016
Depositing User: Mary Creegan
Date Deposited: 19 Nov 2010 14:20
Last Modified: 06 Feb 2018 13:02
URI: http://archive.lstmed.ac.uk/id/eprint/1687

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