Inhibition of angiogenesis and of erythroid differentiation by artemisinin derivatives

Artemisinin derivatives are very active and safe antimalarials, presently used in several therapeutic protocols in combination with quinolines or antifolates drugs. However, in animal models, artemisinins show neurotoxic and embryotoxic effects. Embryotoxicity seems to be due to inhibition of vasculogenesis and erythropoiesis in fetal rats (Longo et al 2005). Anti-angiogenic effects of artemisinins have already been described in vivo and in vitro in tumor models. In the search of new antimalarials, it is crucial to develop safe drugs to be used during malaria episodes in pregnancy. Artemisone is a semi-synthetic derivative of dihydroartemisinin (DHA), 10 times more active against P.falciparum in vitro and less neurotoxic. Here, we report that, compared to DHA, artemisone is also less inhibitory for endothelial cell proliferation and erythroid cell differentiation in vitro. Proliferation, tube formation on Matrigel, vessel formation from rat aortic ring and production of angiogenic cytokines were evaluated on both human umbilical vein endothelial cells (HUVEC) and microvascular endothelial cells (HMEC-1) treated with artemisone or DHA. Artemisone appears to be significantly less toxic than DHA. Similarly, artemisone appears to be less effective as inhibitor of hemin-induced erythroid differentiation of K562 cells suggesting a possible use against malaria in pregnancy.