J. H. Ch'ngY. Q. LeeS. Y. GunW. N. ChiaZ. W. ChangL. K. WongK. T. BattyB. RussellF. NostenL. ReniaK. S.W. TanNational University of SingaporeKarolinska University HospitalNUS Graduate School for Integrative Sciences and EngineeringAgency for Science, Technology and Research, SingaporeCurtin UniversityWest Coast InstituteMahidol UniversityNuffield Department of Clinical Medicine2018-11-092018-11-092014-01-01Cell Death and Disease. Vol.5, No.6 (2014)204148892-s2.0-84903766653https://repository.li.mahidol.ac.th/handle/123456789/33514An alternative antimalarial pathway of an 'outdated' drug, chloroquine (CQ), may facilitate its return to the shrinking list of effective antimalarials.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.Mahidol UniversityBiochemistry, Genetics and Molecular BiologyImmunology and MicrobiologyNeuroscienceArticleSCOPUS10.1038/cddis.2014.265