Current perspectives on the mechanism of action of artemisinins.
Artemisinin derivatives are the most recent single drugs approved and introduced for public antimalarial treatment. Although their recommended use is for treatment of Plasmodium falciparum infection, these drugs also act against other parasites, as well as against tumor cells. The mechanisms of action attributed to artemisinin include interference with parasite transport proteins, disruption of parasite mitochondrial function, modulation of host immune function and inhibition of angiogenesis. Artemisinin combination therapies are currently the preferred treatment for malaria. These combinations may prevent the induction of parasite drug resistance. However, in view of the multiple mechanisms involved, especially when additional drugs are used, the combined therapy should be carefully examined for antagonistic effects. It is now a general theory that the crucial mechanism is interference with plasmodial SERCA. Therefore, future development of resistance may be associated with overproduction or mutations of this transporter. However, a general mechanism, such as alterations in general drug transport pathways, is feasible. In this article, we review the evidence for each mechanism of action suggested.
Golenser
Jacob
J
Department of Parasitology - The Kuvin Centre for the Study of Infectious and Tropical Diseases, The Hebrew University of Jerusalem, Jerusalem 91120, Israel. golenser@md.huji.ac.il
Waknine
Judith H
JH
Krugliak
Miriam
M
Hunt
Nicholas H
NH
Grau
Georges E
GE
D000818:Animals; D000962:Antimalarials / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D037621:Artemisinins / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D004351:Drug Resistance / Q000187:drug effects; D004579:Electron Transport / Q000187:drug effects; D006801:Humans; D007107:Immune System / Q000187:drug effects; D008288:Malaria / Q000188:drug therapy*; D016778:Malaria, Falciparum / Q000188:drug therapy; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism
D000962:Antimalarials; D037621:Artemisinins; D017382:Reactive Oxygen Species; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases