Chemosensitization potential of P-glycoprotein inhibitors in malaria parasites

•A BODIPY-chloroquine probe was synthesized for live cell imaging of CQ efflux dynamics.•This probe accumulates in the DV of chloroquine-sensitive but not in MDR parasites.•Co-treatments with chloroquine or P-gp inhibitors results in probe efflux inhibition.•The chemosensitizing effects of P-gp inhi...

Full description

Saved in:

Bibliographic Details
Published in:	Experimental parasitology Vol. 134; no. 2; pp. 235 - 243
Main Authors:	Alcantara, Laura M., Kim, Junwon, Moraes, Carolina B., Franco, Caio H., Franzoi, Kathrin D., Lee, Sukjun, Freitas-Junior, Lucio H., Ayong, Lawrence S.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-06-2013
Subjects:	ABC transporters Antimalarials - pharmacology artemisinin Artemisinins - pharmacology ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors Benzamides - pharmacology Boron Compounds - chemistry chemosensitization Chemosensitization potentials chloroquine Chloroquine - pharmacology Chlorpheniramine - pharmacology combination drug therapy Dibenzocycloheptenes - pharmacology Drug Interactions Drug Resistance, Multiple drug synergism Erythrocytes - parasitology fluorescence Fluorescent Dyes - chemistry Humans Imatinib Mesylate malaria mechanistic models Mefloquine - pharmacology multiple drug resistance P-glycoprotein inhibitors parasites parasitology Piperazines - pharmacology Plasmodium falciparum Plasmodium falciparum - drug effects Plasmodium falciparum - metabolism Protein Kinase Inhibitors - pharmacology Pyrimidines - pharmacology Quinazolines - pharmacology Quinolines - pharmacology tyrosine vacuoles Chemosensitization potentials P-glycoprotein inhibitors Plasmodium falciparum
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	•A BODIPY-chloroquine probe was synthesized for live cell imaging of CQ efflux dynamics.•This probe accumulates in the DV of chloroquine-sensitive but not in MDR parasites.•Co-treatments with chloroquine or P-gp inhibitors results in probe efflux inhibition.•The chemosensitizing effects of P-gp inhibitors depends on antimalarial drug mechanisms. 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.
Bibliography:	http://dx.doi.org/10.1016/j.exppara.2013.03.022
ISSN:	0014-4894 1090-2449
DOI:	10.1016/j.exppara.2013.03.022