PMID- 26503982
OWN - NLM
STAT- MEDLINE
DCOM- 20160712
LR  - 20160224
IS  - 1537-6613 (Electronic)
IS  - 0022-1899 (Linking)
VI  - 213
IP  - 5
DP  - 2016 Mar 1
TI  - Verapamil-Sensitive Transport of Quinacrine and Methylene Blue via the Plasmodium 
      falciparum Chloroquine Resistance Transporter Reduces the Parasite's 
      Susceptibility to these Tricyclic Drugs.
PG  - 800-10
LID - 10.1093/infdis/jiv509 [doi]
AB  - BACKGROUND: It is becoming increasingly apparent that certain mutations in the 
      Plasmodium falciparum chloroquine resistance transporter (PfCRT) alter the 
      parasite's susceptibility to diverse compounds. Here we investigated the 
      interaction of PfCRT with 3 tricyclic compounds that have been used to treat 
      malaria (quinacrine [QC] and methylene blue [MB]) or to study P. falciparum 
      (acridine orange [AO]). METHODS: We measured the antiplasmodial activities of QC, 
      MB, and AO against chloroquine-resistant and chloroquine-sensitive P. falciparum 
      and determined whether QC and AO affect the accumulation and activity of 
      chloroquine in these parasites. We also assessed the ability of mutant 
      (PfCRT(Dd2)) and wild-type (PfCRT(D10)) variants of the protein to transport QC, 
      MB, and AO when expressed at the surface of Xenopus laevis oocytes. RESULTS: 
      Chloroquine resistance-conferring isoforms of PfCRT reduced the susceptibility of 
      the parasite to QC, MB, and AO. In chloroquine-resistant (but not 
      chloroquine-sensitive) parasites, AO and QC increased the parasite's accumulation 
      of, and susceptibility to, chloroquine. All 3 compounds were shown to bind to 
      PfCRT(Dd2), and the transport of QC and MB via this protein was saturable and 
      inhibited by the chloroquine resistance-reverser verapamil. CONCLUSIONS: Our 
      findings reveal that the PfCRT(Dd2)-mediated transport of tricyclic antimalarials 
      reduces the parasite's susceptibility to these drugs.
CI  - (c) The Author 2015. Published by Oxford University Press for the Infectious 
      Diseases Society of America. All rights reserved. For permissions, e-mail 
      journals.permissions@oup.com.
FAU - van Schalkwyk, Donelly A
AU  - van Schalkwyk DA
AD  - Research School of Biology, Australian National University, Canberra, Australia.
FAU - Nash, Megan N
AU  - Nash MN
AD  - Research School of Biology, Australian National University, Canberra, Australia.
FAU - Shafik, Sarah H
AU  - Shafik SH
AD  - Research School of Biology, Australian National University, Canberra, Australia.
FAU - Summers, Robert L
AU  - Summers RL
AD  - Research School of Biology, Australian National University, Canberra, Australia.
FAU - Lehane, Adele M
AU  - Lehane AM
AD  - Research School of Biology, Australian National University, Canberra, Australia.
FAU - Smith, Peter J
AU  - Smith PJ
AD  - Division of Pharmacology, Department of Medicine, University of Cape Town, 
      Rondebosch, South Africa.
FAU - Martin, Rowena E
AU  - Martin RE
AD  - Research School of Biology, Australian National University, Canberra, Australia.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20151026
PL  - United States
TA  - J Infect Dis
JT  - The Journal of infectious diseases
JID - 0413675
RN  - 0 (Antimalarials)
RN  - 0 (Membrane Transport Proteins)
RN  - 0 (PfCRT protein, Plasmodium falciparum)
RN  - 0 (Protozoan Proteins)
RN  - CJ0O37KU29 (Verapamil)
RN  - H0C805XYDE (Quinacrine)
RN  - T42P99266K (Methylene Blue)
SB  - IM
MH  - Animals
MH  - Antimalarials/pharmacology
MH  - Biological Transport/drug effects
MH  - Drug Resistance
MH  - Gene Expression Regulation/physiology
MH  - Genetic Variation
MH  - Membrane Transport Proteins/*metabolism
MH  - Methylene Blue/*metabolism
MH  - Oocytes/metabolism
MH  - Plasmodium falciparum/*drug effects/*metabolism
MH  - Protozoan Proteins/*metabolism
MH  - Quinacrine/*metabolism
MH  - Verapamil/*pharmacology
MH  - Xenopus laevis
OTO - NOTNLM
OT  - PfCRT
OT  - Plasmodium falciparum
OT  - Xenopus oocytes
OT  - drug resistance
OT  - fluorescence-based transport assay
OT  - methylene blue
OT  - tricyclic drug
EDAT- 2015/10/28 06:00
MHDA- 2016/07/13 06:00
CRDT- 2015/10/28 06:00
PHST- 2015/09/04 00:00 [received]
PHST- 2015/10/15 00:00 [accepted]
PHST- 2015/10/28 06:00 [entrez]
PHST- 2015/10/28 06:00 [pubmed]
PHST- 2016/07/13 06:00 [medline]
AID - jiv509 [pii]
AID - 10.1093/infdis/jiv509 [doi]
PST - ppublish
SO  - J Infect Dis. 2016 Mar 1;213(5):800-10. doi: 10.1093/infdis/jiv509. Epub 2015 Oct 
      26.