title: Drug-induced death of the asexual blood stages of Plasmodium falciparum occurs without typical signs of apoptosis.
abstract: There is clear evidence that most antimalarial drugs, while acting through different mechanisms, are associated with parasite growth/development inhibition and eventual parasite death. However, the exact mode of parasite death remains unclear. In the present study, we investigated the ability of various drugs, including two antimalarial drugs (chloroquine and atovaquone), a topoisemerase II inhibitor (etoposide) and a nitric oxide donor (S-nitro-N-acetyl-D, L-penicillamine), to induce apoptosis in a laboratory strain of Plasmodium falciparum. Results obtained from flow cytometric analysis showed a significant reduction in the percent of parasitemia and parasite growth in all drug-treated parasite cultures, including those treated with etoposide and S-nitro-N-acetyl-D, L-penicillamine. For further investigation, we used various biochemical approaches including the terminal dUTP nick-end labeling assay, determination of mitochondrial membrane integrity and DNA degradation/fragmentation, to analyze the changes occurring during parasite-drug interactions and eventual death. We observed that loss of membrane potential was induced in parasite cultures treated with atovaquone, while S-nitro-N-acetyl-D, L-penicillamine induced abnormal parasite forms, "crisis forms", and minor DNA degradation. However, these features were not observed in the parasite cultures treated with chloroquine nor were other features of apoptosis-like death associated with any of the drugs used in this study. The death resulting from the various drug treatments is atypical of apotosis. More studies will be needed to define the precise mode of death exhibited by P. falciparum.
authors.affiliation: Department of Immunology Wenner-Gren Institute, Stockholm University, Stockholm, Sweden. alice.nyakeriga@cchmc.org
authors.forename: Alice M
authors.initials: AM
authors.lastname: Nyakeriga
authors.forename: Hedvig
authors.initials: H
authors.lastname: Perlmann
authors.forename: Margareta
authors.initials: M
authors.lastname: Hagstedt
authors.forename: Klavs
authors.initials: K
authors.lastname: Berzins
authors.forename: Marita
authors.initials: M
authors.lastname: Troye-Blomberg
authors.forename: Boris
authors.initials: B
authors.lastname: Zhivotovsky
authors.forename: Peter
authors.initials: P
authors.lastname: Perlmann
authors.forename: Alf
authors.initials: A
authors.lastname: Grandien
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053626:Atovaquone; D002478:Cells, Cultured; D002738:Chloroquine / Q000494:pharmacology; D053938:DNA Fragmentation / Q000187:drug effects; D016054:DNA, Protozoan / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology*; D005047:Etoposide / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D020287:In Situ Nick-End Labeling; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology*; D008564:Membrane Potentials / Q000187:drug effects; D051336:Mitochondrial Membranes / Q000187:drug effects; D009285:Naphthoquinones / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D018512:Parasitemia / Q000469:parasitology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development
chemical_list: D000962:Antimalarials; D016054:DNA, Protozoan; D004791:Enzyme Inhibitors; D009285:Naphthoquinones; D020030:Nitric Oxide Donors; C110881:S-nitro-N-acetylpenicillamine; D005047:Etoposide; D002738:Chloroquine; D010396:Penicillamine; D053626:Atovaquone