The molecular mechanism of action of artemisinin--the debate continues

Abstract

Despite international efforts to 'roll back malaria' the 2008 World Malaria Report revealed the disease still affects approximately 3 billion people in 109 countries; 45 within the WHO African region. The latest report however does provide some 'cautious optimism'; more than one third of malarious countries have documented greater than 50% reductions in malaria cases in 2008 compared to 2000. The goal of the Member States at the World Health Assembly and 'Roll Back Malaria' (RBM) partnership is to reduce the numbers of malaria cases and deaths recorded in 2000 by 50% or more by the end of 2010. Although malaria is preventable it is most prevalent in poorer countries where prevention is difficult and prophylaxis is generally not an option. The burden of disease has increased by the emergence of multi drug resistant (MDR) parasites which threatens the use of established and cost effective antimalarial agents. After a major change in treatment policies, artemisinins are now the frontline treatment to aid rapid clearance of parasitaemia and quick resolution of symptoms. Since artemisinin and its derivatives are eliminated rapidly, artemisinin combination therapies (ACT's) are now recommended to delay resistance mechanisms. In spite of these precautionary measures reduced susceptibility of parasites to the artemisinin-based component of ACT's has developed at the Thai-Cambodian border, a historical 'hot spot' for MDR parasite evolution and emergence. This development raises serious concerns for the future of the artemsinins and this is not helped by controversy related to the mode of action. Although a number of potential targets have been proposed the actual mechanism of action remains ambiguous. Interestingly, artemisinins have also shown potent and broad anticancer properties in cell lines and animal models and are becoming established as anti-schistosomal agents. In this review we will discuss the recent evidence explaining bioactivation and potential molecular targets in the chemotherapy of malaria and cancer.

Figure 1

Antimalarial endoperoxides.

Figure 2

Detoxification of hemoglobin: toxic hematin (formed by hydrogen bonding of heme monomers) [12] is converted by the parasite to an insoluble non-toxic compound called hemozoin (it has recently been suggested that the propionate group of each Fe(III)PPIX molecule coordinates to the Fe(III) centre of its partner) [13].

Figure 3

Bioactivation of artemisinin; A) Reductive scission model; B) Open peroxide model.

Figure 4

Confocal microscope images of parasite-infected red blood cells incubated with fluorescent artemisinin nitrobenzodiazole (NBD) conjugate without iron chelator DFO before (1a) and after wash (1b), and with DFO (100 µM) before (1c) and after wash (1d) [27].

Figure 5

artemisinin dimer 7.

Figure 6

Alkylation of a heme model (the dimethyl ester of heme) by a primary carbon centered radical derived from bioactivation of artemisinin (1). Adducts were also obtained from α and δ carbon atoms [54].

Figure 7

Comparison of the structural and chemical features of sequiterpene lactones artemisinin (1) and thapsigargin (8) [63].