POLYMORPHISM OF THE PLASMODIUM FALCIPARUM MULTIDRUG RESISTANCE AND CHLOROQUINE RESISTANCE TRANSPORTER GENES AND IN VITRO SUSCEPTIBILITY TO AMINOQUINOLINES IN ISOLATES FROM THE PERUVIAN AMAZON

ABSTRACTThe antiretroviral protease inhibitors (APIs) ritonavir, saquinavir, and lopinavir, used to treat HIV infection, inhibit the growth ofPlasmodium falciparumat clinically relevant concentrations. Moreover, it has been reported that these APIs potentiate the activity of chloroquine (CQ) against this parasitein vitro. The mechanism underlying this effect is not understood, but the degree of chemosensitization varies between the different APIs and, with the exception of ritonavir, appears to be dependent on the parasite exhibiting a CQ-resistant phenotype. Here we report a study of the role of theP. falciparumchloroquine resistance transporter (PfCRT) in the interaction between CQ and APIs, using transgenic parasites expressing different PfCRT alleles and using theXenopus laevisoocyte system for the heterologous expression of PfCRT. Our data demonstrate that saquinavir behaves as a CQ resistance reverser and that this explains, at least in part, its ability to enhance the effects of CQ in CQ-resistantP. falciparumparasites.

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ASSOCIATION BETWEEN MUTATIONS IN PLASMODIUM FALCIPARUM CHLOROQUINE RESISTANCE TRANSPORTER AND P. FALCIPARUM MULTIDRUG RESISTANCE 1 GENES AND IN VIVO AMODIAQUINE RESISTANCE IN P. FALCIPARUM MALARIA–INFECTED CHILDREN IN NIGERIA

American Journal of Tropical Medicine and Hygiene ◽

10.4269/ajtmh.2006.75.155 ◽

2006 ◽

Vol 75 (1) ◽

pp. 155-161 ◽

Cited By ~ 63

Author(s):

C. T. HAPPI ◽

D. E. KYLE ◽

A. SOWUNMI ◽

G. O. GBOTOSHO ◽

A. M. J. ODUOLA ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Multidrug Resistance ◽

Falciparum Malaria ◽

Chloroquine Resistance ◽

Chloroquine Resistance Transporter

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Bisbenzylisoquinolines as modulators of chloroquine resistance in Plasmodium falciparum and multidrug resistance in tumor cells.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.6.1476 ◽

1996 ◽

Vol 40 (6) ◽

pp. 1476-1481 ◽

Cited By ~ 34

Author(s):

F Frappier ◽

A Jossang ◽

J Soudon ◽

F Calvo ◽

P Rasoanaivo ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Multidrug Resistance ◽

Tumor Cells ◽

Synergistic Effects ◽

Cancer Cell Line ◽

Multidrug Resistant ◽

Chloroquine Resistance ◽

Naturally Occurring ◽

Structure Activity

Ten naturally occurring bisbenzylisoquinolines (BBIQ) and two dihydro derivatives belonging to five BBIQ subgroups were evaluated in vitro for their ability to inhibit Plasmodium falciparum growth and, in drug combination, to reverse the resistance to chloroquine of strain FcB1. The same alkaloids were also assessed in vitro for their potentiating activity against vinblastine with the multidrug-resistant clone CCRF-CEM/VLB, established from lymphoblastic acute leukemia. Three of the BBIQ tested had 50% inhibitory concentrations of less than 1 microM. The most potent antimalarial agent was cocsoline (50% inhibitory concentration, 0.22 microM). Regarding the chloroquine-potentiating effect, fangchinoline exhibited the highest biological activity whereas the remaining compounds displayed either antagonistic or slight synergistic effects. Against the multidrug-resistant cancer cell line, fangchinoline was also by far the most active compound. Although there were clear differences between the activities of tested alkaloids, no relevant structure-activity relationship could be established. Nevertheless, fangchinoline appears to be a new biochemical tool able to help in the comprehension of the mechanism of both chloroquine resistance in P. falciparum and multidrug resistance in tumor cells.

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