Effect of dihydroartemisinin on human Erythroid cell differentiation

Women in their first pregnancy are at the very high-risk of developing severe malaria which includes maternal anemia, low birth weight of newborns and increased mortality of both mother and infants. The WHO recommends the Intermittent Preventive Treatment to cure malaria during gestation, but drug safety in pregnancy is an issue. Artemisinin combination therapy is the first line treatment for uncomplicated malaria, but artemisinin derivatives carry a potential toxic effect on embryos. In animal studies they affect embryonic erythroid precursors only on certain days of gestation. This suggests that the target of DHA toxicity could be the primitive erythropoiesis. Our aim was to study the effect of artemisinin and 4-aminoquinoline derivatives on in vitro models which reproduce human erythropoiesis: K562 leukemia cells and CD34+ from human peripheral blood. Cells switch from fetal and embryonic to adult hemoglobin in presence of hemin or butyric acid (K562) or erythropoietin (CD34+). We found that artemisinins inhibit both cell growth and erythroid differentiation (P<0.05), measured as adult hemoglobin synthesis and erythroblasts count. The effect is dose and time-dependent. DHA, which is the active metabolite of artemisinins, has the strongest effect. As expected chloroquine and amodiaquine did not affect cell differentiation, confirming the suitability of the models for studying drug toxicity on developmental erythropoiesis. Moreover, as in animal studies, our results show that a toxic effect of DHA could occur if administered during first trimester of pregnancy, when fetal blood consists mostly of primitive erythroblasts. The support of EU Antimal Project 18834 is acknowledged