title: Validation of a chloroquine-induced cell death mechanism for clinical use against malaria.
abstract: An alternative antimalarial pathway of an 'outdated' drug, chloroquine (CQ), may facilitate its return to the shrinking list of effective antimalarials. Conventionally, CQ is believed to interfere with hemozoin formation at nanomolar concentrations, but resistant parasites are able to efflux this drug from the digestive vacuole (DV). However, we show that the DV membrane of both resistant and sensitive laboratory and field parasites is compromised after exposure to micromolar concentrations of CQ, leading to an extrusion of DV proteases. Furthermore, only a short period of exposure is required to compromise the viability of late-stage parasites. To study the feasibility of this strategy, mice malaria models were used to demonstrate that high doses of CQ also triggered DV permeabilization in vivo and reduced reinvasion efficiency. We suggest that a time-release oral formulation of CQ may sustain elevated blood CQ levels sufficiently to clear even CQ-resistant parasites.
authors: 1] Department of Microbiology, National University of Singapore, 5 Science Drive 2, Singapore, Singapore [2] Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Nobels väg 16, KI Solna Campus, Box 280, Stockholm, Sweden.
authors: J-H
authors: JH
authors: Ch'ng
authors: 1] Department of Microbiology, National University of Singapore, 5 Science Drive 2, Singapore, Singapore [2] NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Centre for Life Sciences (CeLS), #05-01, 28 Medical Drive, Singapore, Singapore.
authors: Y-Q
authors: YQ
authors: Lee
authors: Singapore Immunology Network, Agency for Science Technology and Research (A*STAR), Biopolis, 8A Biomedical Grove, Immunos Building, Level 4, Singapore, Singapore.
authors: S Y
authors: SY
authors: Gun
authors: Singapore Immunology Network, Agency for Science Technology and Research (A*STAR), Biopolis, 8A Biomedical Grove, Immunos Building, Level 4, Singapore, Singapore.
authors: W-N
authors: WN
authors: Chia
authors: Singapore Immunology Network, Agency for Science Technology and Research (A*STAR), Biopolis, 8A Biomedical Grove, Immunos Building, Level 4, Singapore, Singapore.
authors: Z-W
authors: ZW
authors: Chang
authors: Department of Chemistry, National University of Singapore, Block S8, Level 3, 3 Science Drive 3, Singapore, Singapore.
authors: L-K
authors: LK
authors: Wong
authors: 1] School of Pharmacy, Curtin University, GPO Box U1987, Perth Western Australia 6845 Bentley, WA, Australia [2] West Coast Institute, 35 Kendrew Crescent, Joondalup, WA, Australia.
authors: K T
authors: KT
authors: Batty
authors: Department of Microbiology, National University of Singapore, 5 Science Drive 2, Singapore, Singapore.
authors: B
authors: B
authors: Russell
authors: 1] Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, 68/30 Bantung Road, PO.BOX 46, Maesot, TAK, Thailand [2] Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Churchill Hospital, Old Road, Oxford, UK.
authors: F
authors: F
authors: Nosten
authors: Singapore Immunology Network, Agency for Science Technology and Research (A*STAR), Biopolis, 8A Biomedical Grove, Immunos Building, Level 4, Singapore, Singapore.
authors: L
authors: L
authors: Renia
authors: Department of Microbiology, National University of Singapore, 5 Science Drive 2, Singapore, Singapore.
authors: K S-W
authors: KS
authors: Tan
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000493:pharmacokinetics / Q000494:pharmacology; D002738:Chloroquine / Q000493:pharmacokinetics / Q000494:pharmacology; D004195:Disease Models, Animal; D004341:Drug Evaluation; D006420:Hemeproteins / Q000378:metabolism; D008288:Malaria / Q000097:blood / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D010961:Plasmodium / Q000378:metabolism*
chemical_list: D000962:Antimalarials; D006420:Hemeproteins; C020753:hemozoin; D002738:Chloroquine