Modulation of a Schistosoma mansoni multidrug transporter by the antischistosomal drug praziquantel.
P-glycoprotein (Pgp) is an ATP-dependent efflux pump involved in transport of xenobiotics from cells that, when overexpressed, can mediate multidrug resistance in mammalian cells. Pgp may be a candidate target for new anthelmintics, as it plays critical roles in normal cell physiology, in removal of drugs from cells, and potentially in the development of drug resistance. Schistosomes are parasitic flatworms that cause schistosomiasis, which affects hundreds of millions of people worldwide. Here, we express SMDR2, a Pgp homologue from Schistosoma mansoni (Platyhelminthes), in Chinese hamster ovary (CHO) cells and use fluorescence-based assays to examine the functional and pharmacological properties of this transporter. Membrane vesicles from stably transfected CHO cells expressing recombinant SMDR2 show significant increases in rhodamine transport and ATP hydrolysis compared with those from control cells or cells transfected with empty vector. SMDR2-mediated transport is inhibited by the Pgp modulators verapamil (IC(50)=12.1 muM) and nifedipine, and also by praziquantel, the current drug of choice against schisotosomiasis (IC(50)=17.4 muM). Efflux measurements of a fluorescent analog of praziquantel indicate that it is also a substrate for SMDR2. The interaction of praziquantel with SMDR2 may offer new strategies for potentiating the action of praziquantel and possibly overcoming drug resistance.
Kasinathan
Ravi S
RS
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce St., Philadelphia, PA 19104, USA.
Goronga
Tinopiwa
T
Messerli
Shanta M
SM
Webb
Thomas R
TR
Greenberg
Robert M
RM
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D017931:DNA Primers / Q000235:genetics; D018509:DNA, Helminth / Q000235:genetics; D018432:Drug Resistance, Multiple; D017238:Genes, Helminth; D015801:Helminth Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D011223:Praziquantel / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D012235:Rhodamines / Q000378:metabolism; D012550:Schistosoma mansoni / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D012556:Schistosomicides / Q000494:pharmacology*; D014162:Transfection; D014638:Vanadates / Q000494:pharmacology; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D000251:Adenosine Triphosphatases; D000255:Adenosine Triphosphate; D017931:DNA Primers; D018509:DNA, Helminth; D015801:Helminth Proteins; D011223:Praziquantel; D011994:Recombinant Proteins; D012235:Rhodamines; D012556:Schistosomicides; D014638:Vanadates; D000097202:ATP-Binding Cassette Sub-Family B Member 4