title: Chemosensitization potential of P-glycoprotein inhibitors in malaria parasites.
abstract: Members of the ATP-binding cassette (ABC)-type transporter superfamily have been implicated in multidrug resistance in malaria, and various mechanistic models have been postulated to explain their interaction with diverse antimalarial drugs. To gain insight into the pharmacological benefits of inhibiting ABC-type transporters in malaria chemotherapy, we investigated the in vitro chemosensitization potential of various P-glycoprotein inhibitors. A fluorescent chloroquine derivative was synthesized and used to assess the efflux dynamics of chloroquine in MDR and wild type Plasmodium falciparum parasites. This novel BODIPY-based probe accumulated in the digestive vacuole (DV) of CQ-sensitive parasites but less so in MDR cells. Pre-exposure of the MDR parasites to non-cytocidal concentrations of unlabeled chloroquine resulted in a diffused cytoplasmic retention of the probe whereas a similar treatment with the CQR-reversing agent, chlorpheniramine, resulted in DV accumulation. A diffused cytoplasmic distribution of the probe was also obtained following treatment with the P-gp specific inhibitors zosuquidar and tariquidar, whereas treatments with the tyrosine kinase inhibitors gefitinib or imatinib produced a partial accumulation within the DV. Isobologram analyses of the interactions between these inhibitors and the antimalarial drugs chloroquine, mefloquine, and artemisinin revealed distinct patterns of drug synergism, additivity and antagonism. Taken together, the data indicate that competitive tyrosine kinase and noncompetitive P-glycoprotein ATPase-specific inhibitors represent two new classes of chemosensitizing agents in malaria parasites, but caution against the indiscriminate use of these agents in antimalarial drug combinations.
authors.affiliation: Center for Neglected Diseases Drug Discovery, Institut Pasteur Korea, Sampyeong-dong 696, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Alcantara
authors.forename: Junwon
authors.initials: J
authors.lastname: Kim
authors.forename: Carolina B
authors.initials: CB
authors.lastname: Moraes
authors.forename: Caio H
authors.initials: CH
authors.lastname: Franco
authors.forename: Kathrin D
authors.initials: KD
authors.lastname: Franzoi
authors.forename: Sukjun
authors.initials: S
authors.lastname: Lee
authors.forename: Lucio H
authors.initials: LH
authors.lastname: Freitas-Junior
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Ayong
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D001896:Boron Compounds / Q000737:chemistry; D002738:Chloroquine / Q000494:pharmacology; D002744:Chlorpheniramine / Q000494:pharmacology; D003986:Dibenzocycloheptenes / Q000494:pharmacology; D004347:Drug Interactions; D018432:Drug Resistance, Multiple; D004912:Erythrocytes / Q000469:parasitology; D005456:Fluorescent Dyes / Q000737:chemistry; D000077156:Gefitinib; D006801:Humans; D000068877:Imatinib Mesylate; D015767:Mefloquine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology
chemical_list: C095489:4,4-difluoro-4-bora-3a,4a-diaza-s-indacene; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000962:Antimalarials; D037621:Artemisinins; D001549:Benzamides; D001896:Boron Compounds; D003986:Dibenzocycloheptenes; D005456:Fluorescent Dyes; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; D011804:Quinolines; D002744:Chlorpheniramine; C095179:zosuquidar trihydrochloride; D002738:Chloroquine; D000068877:Imatinib Mesylate; C031327:artemisinin; C402343:tariquidar; D000077156:Gefitinib; D015767:Mefloquine