Modulation of a Schistosoma mansoni multidrug transporter by the antischistosomal drug praziquantel

Ravi S. Kasinathan, Tinopiwa Goronga, Shanta M. Messerli, Thomas R. Webb, Robert M. Greenberg

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)128-135
Number of pages8
JournalFASEB Journal
Volume24
Issue number1
DOIs
StatePublished - Jan 2010
Externally publishedYes

Keywords

  • Drug resistance
  • Efflux transporter
  • Verapamil

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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