title: Malagashanine potentiates chloroquine antimalarial activity in drug resistant Plasmodium malaria by modifying both its efflux and influx.
abstract: Malagashanine (MG) is the parent compound of the new N(b)-C(21) seco-curan alkaloids isolated hitherto from Madagascan Strychnos. On account of its promising chemosensitizing activity against chloroquine (CQ)-resistant Plasmodium falciparum (Pf) strains, we investigated its mechanism of action. One prominent result was the finding that MG significantly increased the accumulation of [3H]-chloroquine in chloroquine resistant (CQR) K1 and FCM29 Pf strains at mid and old trophozoite stages. This effect was concentration-dependent and not observed in chloroquine sensitive (CQS) strains. Comparative monitoring of the release of [3H]-CQ from pre-loaded CQR and CQS Pf strains revealed strong concentration-dependent inhibition of CQ release by MG from the pre-loaded CQR FCM29 strain. We also found that MG substantially inhibited the loss of pre-accumulated CQ in the resistant K1 strain after a washing procedure at 4 degrees C. On the other hand, we observed that the addition of glucose at the old trophozoite stage induced a rapid increase in CQ accumulation in the CQS 3D7 strain cultured in glucose-free medium, but not in the CQR FCM29 strain. Interestingly, MG considerably increased (>100%) CQ accumulation in the FCM29 strain in a glucose-free medium while the addition of glucose further significantly increased this accumulation. Our study therefore clearly demonstrates that MG prevents CQ efflux from, and stimulates CQ influx into, drug-resistant Pf. Overall, MG appears to be a useful lead for the design and synthesis of more powerful and effective resistance modulators.
authors.affiliation: Laboratoire de Pharmacognosie Appliquée aux Maladies Infectieuses et Parasitaires, Institut Malgache de Recherches Appliquées, BP 3833, Antananarivo 101, Madagascar.
authors.forename: David
authors.initials: D
authors.lastname: Ramanitrahasimbola
authors.forename: Philippe
authors.initials: P
authors.lastname: Rasoanaivo
authors.forename: Suzanne
authors.initials: S
authors.lastname: Ratsimamanga
authors.forename: Henri
authors.initials: H
authors.lastname: Vial
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000378:metabolism* / Q000494:pharmacology; D002738:Chloroquine / Q000378:metabolism* / Q000494:pharmacology; D003470:Culture Media / Q000737:chemistry; D004351:Drug Resistance / Q000187:drug effects; D004357:Drug Synergism; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology; D005947:Glucose / Q000494:pharmacology; D019271:Hypoxanthine / Q000378:metabolism; D008018:Life Cycle Stages / Q000187:drug effects / Q000502:physiology; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D013997:Time Factors
chemical_list: D000470:Alkaloids; D000962:Antimalarials; D003470:Culture Media; C103769:malagashanine; D019271:Hypoxanthine; D002738:Chloroquine; D005947:Glucose