DHA inhibits human erythroid cell differentiation by altering the GATA switch

WHO recommends to avoid artemisinin treatment during the first trimester of pregnancy, because animal models showed a significant depletion of embryonic red cells, which occurs only during a specific days of gestation. We recently demonstrated for the first time that DHA, which is the in vivo metabolite of many artemisinin derivatives, inhibits human erythroid cell differentiation, as well. We showed that DHA specifically targets the pro and basophilic erythroblasts during in vitro erythroid cell differentiation of CD34+ stem cells. By using K562 cells differentiated toward the erythroid lineages by chemical inducers and by comparing the effects of several artemisinins, we confirmed that DHA is the most toxic compound of this drug family. Significant reduction by DHA was observed not only of cell growth, but also of erythroid cell maturation, as shown by the changes in cell viability, cell cycle progression, GpA expression, inhibition of γ-globin gene and GATA-1 mRNAs. In addition, we observed that the toxicity is related to pathways which regulate the haemoglobin synthesis. In fact, DHA rapidly induces the release of Cytochrome C from the mitochondria, which in turn, activates Caspase-3 and, together with the HSP70 down regulation, induces the GATA-1 cleavage and the up-regulation of GATA-2. In conclusion, altering the GATA switch, DHA modifies the fate of the erythroid cell: it prevents the erythroid cell differentiation and simultaneously causes the arrest of cell growth and, eventually, the cell death through apoptosis. This dual effect is clearly dose-dependent. In conclusion, our results support WHO recommendations and the urgent need to better define the risk-benefit of the use of artemisinins treatment for malaria during the first trimester of human pregnancy.