TY - JOUR
T1 - Modulation of a Schistosoma mansoni multidrug transporter by the antischistosomal drug praziquantel
AU - Kasinathan, Ravi S.
AU - Goronga, Tinopiwa
AU - Messerli, Shanta M.
AU - Webb, Thomas R.
AU - Greenberg, Robert M.
PY - 2010/1
Y1 - 2010/1
N2 - 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 (IC50=12.1 μM) and nifedipine, and also by praziquantel, the current drug of choice against schisotosomiasis (IC50=17.4 μM). 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, R. S., Goronga, T., Messerli, S. M., Webb, T. R., Greenberg, R. M. Modulation of a Schistosoma mansoni multidrug transporter by the antischistosomal drug praziquantel.
AB - 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 (IC50=12.1 μM) and nifedipine, and also by praziquantel, the current drug of choice against schisotosomiasis (IC50=17.4 μM). 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, R. S., Goronga, T., Messerli, S. M., Webb, T. R., Greenberg, R. M. Modulation of a Schistosoma mansoni multidrug transporter by the antischistosomal drug praziquantel.
KW - Drug resistance
KW - Efflux transporter
KW - Verapamil
UR - http://www.scopus.com/inward/record.url?scp=75149198677&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=75149198677&partnerID=8YFLogxK
U2 - 10.1096/fj.09-137091
DO - 10.1096/fj.09-137091
M3 - Article
C2 - 19726755
AN - SCOPUS:75149198677
SN - 0892-6638
VL - 24
SP - 128
EP - 135
JO - FASEB Journal
JF - FASEB Journal
IS - 1
ER -