Trends in Parasitology
Research FocusTherapeutic potential of folate uptake inhibition in Plasmodium falciparum
Section snippets
Inhibition of folate uptake
In P. falciparum, studies have demonstrated that the addition of folate derivatives (folic acid or folinic acid) decreases the activity of antifolate drugs, both in vitro and in vitro 6, 7, 8. Likewise, the lowering of folate concentration in in vitro culture medium enhances the activity of antifolate antimalarial agents 9, 10. This clearly shows that folate uptake contributes significantly to antifolate drug efficacy. Therefore, it is surprising that inhibition of the folate uptake pathway has
Effect of probenecid on antifolate activity in vitro
The effect and the impact of PBN on the activity of antimalarial antifolates in vitro and on the uptake of folic acid into the parasitized erythrocyte, respectively, have been assessed.
Possible mode of action of probenecid
There have been several studies investigating the mode of action of PBN in mammalian cells (cancer cells). PBN has two effects on cancer cells: (i) PBN reverses methotrexate resistance [20]; and (ii) PBN increases the activity of other antifolates [11]. Molecular analyses have shown that the ability of PBN to reverse methotrexate resistance is associated with the inhibition of MRPs. MRPs are overexpressed in methotrexate-resistant cells, which is correlated to an increase of methotrexate
A potential therapeutic strategy?
PBN has been available for >50 years and is still used for a range of clinical conditions (e.g. the management of gout) and in combination with penicillin to increase the duration of penicillin action. Pharmacokinetics properties and the toxicity profile of PBN have been studied extensively [31]. The highest recommended dose of PBN for adults is 3 g. A dose of 2 g (normal dose) yields circulating plasma concentrations ranging between 500 and 700 μM. At these therapeutic doses, PBN has an
Conclusion
For the first time, it has been reported that PBN, an inhibitor of anion transporter, has the ability to increase antifolate activity in P. falciparum. However, many questions remain. The relevant transporter(s) needs to be identified and fully characterized as a vital step towards rational potentiator design. The effect of PBN in humans when used with synergistic antifolate combinations should also be assessed, although it is predicted that these effects would be greater than that seen with
Acknowledgements
We thank the director of Kenya Medical Research Institute for permission to publish these data. This work was supported by the Wellcome Trust (no. 056769). A.N. and K.M. are grateful to the Wellcome Trust for personal support. P.W. and S.A.W. are grateful to the Wellcome Trust for institutional support.
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