sphingosine-1-phosphate and artemisinin

In mammalian cells, ceramide mediates death by chemotherapeutic drugs. We analysed, for the first time, the role of ceramide in inhibiting growth of the malaria-causing parasite Plasmodium falciparum. Added exogenously, ceramide significantly decreased the number of parasites, and this effect was abolished by sphingosine-1-phosphate, a biological antagonist of ceramide action. Ceramide can induce death of cancer cells by decreasing glutathione levels, and in our work it induced dose- and time-dependent depletion of glutathione in P. falciparum parasites. N-acetylcysteine, a precursor of glutathione, abrogated the cytotoxic effect of ceramide. Thus, ceramide can mediate growth inhibition of P. falciparum parasites by decreasing glutathione levels. The antimalarial drugs artemisinin and mefloquine induced the death of P. falciparum parasites by sphingomyelinase-generated ceramide and by decreasing parasite glutathione levels. Altogether, ceramide was identified as a signalling molecule capable of inducing growth inhibition of P. falciparum malarial parasites.

Topics: Animals; Antiprotozoal Agents; Apoptosis; Artemisinins; Ceramides; Glutathione; Growth Inhibitors; Lysophospholipids; Malaria, Falciparum; Mefloquine; Plasmodium falciparum; Sesquiterpenes; Sphingomyelin Phosphodiesterase; Sphingosine