Can the iron content of culture media impact on the leishmanicidal effect of artemisinin?

Endoperoxides (EPs) like artemisinin following cleavage of their EP bridge can kill parasites via generation of carbon-centered radicals. As the presence of low molecular mass iron and/or heme is crucial, this study aimed to establish the influence of iron on the leishmanicidal action of artemisinin when present in differing amounts in culture media. In promastigotes cultured in Schneiders insect medium (SIM), that had a 8.0-fold higher amount of iron as compared to Medium 199 (M199), the impact of artemisinin on cell viability, redox status, labile iron pool (LIP), and Annexin-V positivity was evaluated. In SIM, the IC50 of artemisinin was 25.50-fold lower than M199, and in both media its cytotoxicity was decreased by the addition of hemin or following chelation of Fe2+ by Deferoxamine (DFO). In SIM vis-a-vis M199, artemisinin caused a greater redox imbalance which translated into a higher degree of externalization of phosphatidylserine and depletion of the LIP. The presence of a higher proportion of iron in SIM as compared to M199 significantly enhanced the cytotoxicity of artemisinin in Leishmania promastigotes, and was attributed to a higher degree of iron-mediated cleavage of its EP bridge that led to a higher generation of free radicals.