Semisynthetic
artemisinin-based
therapies are the first-line treatment for P.
falciparum malaria, but next-generation
synthetic drug candidates are urgently required to improve availability and respond to the emergence of
artemisinin-resistant parasites.
Artemisinins are embryotoxic in animal models and induce apoptosis in sensitive mammalian cells. Understanding the cytotoxic propensities of
antimalarial drug candidates is crucial to their successful development and utilization. Here, we demonstrate that, similarly to the model
artemisinin artesunate (ARS), a synthetic tetraoxane
drug candidate (RKA182) and a trioxolane equivalent (FBEG100) induce embryotoxicity and depletion of primitive erythroblasts in a rodent model. We also show that RKA182, FBEG100 and ARS are cytotoxic toward a panel of established and primary human cell lines, with caspase-dependent apoptosis and
caspase-independent
necrosis underlying the induction of cell death. Although the toxic effects of RKA182 and FBEG100 proceed more rapidly and are relatively less cell-selective than that of ARS, all three compounds are shown to be dependent upon
heme,
iron and oxidative stress for their ability to induce cell death. However, in contrast to previously studied
artemisinins, the toxicity of RKA182 and FBEG100 is shown to be independent of general chemical decomposition. Although
tetraoxanes and trioxolanes have shown promise as next-generation
antimalarials, the data described here indicate that adverse effects associated with
artemisinins, including embryotoxicity, cannot be ruled out with these novel compounds, and a full understanding of their toxicological actions will be central to the continuing design and development of safe and effective
drug candidates which could prove important in the fight against
malaria.