Effect of folate derivatives on the activity of antifolate drugs used against malaria and cancer

Abstract

The folate derivatives folic acid (FA) and folinic acid (FNA) decrease the in vivo and in vitro activities of antifolate drugs in Plasmodium falciparum. However, the effects of 5-methyl-tetrahydrofolate (5-Me-THF) and tetrahydrofolate (THF), the two dominant circulating folate forms in humans, have not been explored yet. We have investigated the effects of FA, FNA, 5-Me-THF, and THF on the in vitro activity of the antimalarial antifolates pyrimethamine and chlorcycloguanil and the anticancer antifolates methotrexate (MTX), aminopterin, and trimetrexate (TMX), against P. falciparum. The results indicate that these anticancers are potent against P. falciparum, with IC 50 <50 nM. 5-Me-THF does not significantly decrease the activity of all tested drugs, and none of the tested folate derivatives significantly decrease the activity of these anticancers. Thus, malaria folate metabolism has features different from those in human, and the exploitation of this difference could lead to the discovery of new drugs to treat malaria. For instance, the combination of 5-Me-THF with a low dose of TMX could be used to treat malaria. In addition, the safety of a low dose of MTX in the treatment of arthritis indicates that this drug could be used alone to treat malaria.

Safety and benefits of interventions to increase folate status in malaria‐endemic areas

“…The evidence suggesting that oral 5‐methyl‐THF may act as a source of folates in humans without antagonising the activity of antifolate drugs against P. falciparum (Nduati et al , 2008) is promising but it is derived from a single in vitro study with only two P. falciparum laboratory strains.…”

“…In theory, 5‐methyl‐ THF is a methyl donor in the methionine cycle (lower cycle, with metabolites in green), resulting in the production of tetrahydrofolate and methionine (blue dotted lines). Recent evidence from an in vitro study suggests, however, that this pathway is not effectively utilised in Plasmodium , either because 5‐methyl‐ THF monoglutamate from the erythrocytic pool cannot cross the membranes of the parasitophorous vacuole and the parasite (blue dotted line, with question mark) or because the parasite does not need methionine, because it derives this amino acid precursor of S‐adenosylmethionine from haemoglobin degradation or human plasma (Nduati et al , 2008). This evidence suggests that oral 5‐methyl‐ THF may act as a source of folates in humans without antagonising the in vitro activity of antifolate drugs against P. falciparum (Nduati et al , 2008; Nzila et al , 2014).…”

“…Recent evidence from an in vitro study suggests, however, that this pathway is not effectively utilised in Plasmodium , either because 5‐methyl‐ THF monoglutamate from the erythrocytic pool cannot cross the membranes of the parasitophorous vacuole and the parasite (blue dotted line, with question mark) or because the parasite does not need methionine, because it derives this amino acid precursor of S‐adenosylmethionine from haemoglobin degradation or human plasma (Nduati et al , 2008). This evidence suggests that oral 5‐methyl‐ THF may act as a source of folates in humans without antagonising the in vitro activity of antifolate drugs against P. falciparum (Nduati et al , 2008; Nzila et al , 2014). DHF : dihydrofolate; DHFR : dihydrofolate reductase; DHPS : dihydropteroate synthase; dTMP : deoxythymidine monophosphate; dUMP : deoxyuridine monophosphate (a deoxynucleotide); pABA : para‐aminobenzoic acid: SAM : S ‐adenosyl methionine; THF : tetrahydrofolate.…”

“…If this pathway were used to produce THF, the parasite could theoretically bypass the inhibition of folate synthesis that is induced by antifolate drugs. An in vitro study recently showed, however, that even at supra‐physiological concentrations, 5‐methyl‐THF hardly antagonised the activity of pyrimethamine and chlorcycloguanil against P. falciparum (Nduati et al , 2008). This finding indicates that either 5‐methyl‐THF is not transported into the parasite cell or that 5‐methyl‐THF is present intracellularly but the de novo methionine pathway is not effectively utilised, perhaps because the parasite can use haemoglobin degradation or human plasma as an alternative source of methionine (Nduati et al , 2008).…”

Effects and safety of periconceptional folate supplementation for preventing birth defects

“…Four controlled trials using different doses have shown that supplementation with 5-MTHF is at least as effective as folic acid in improving folate status in women of childbearing age (Houghton 2006;Lamers 2004;Venn 2002;Venn 2003). This form of folate may also be less likely to mask haematological symptoms of severe vitamin B 12 deficiency and it exhibits a lower interaction potential with antifolate antimalarial drugs (Nduati 2008;Pietrzik 2010), specifically sulphadoxine-pyrimethamine (SP), which might be affected by folic acid supplementation (Carter 2005;English 2006;Van Eijk 2008).…”