Inhibition or Knockdown of ABC Transporters Enhances Susceptibility of Adult and Juvenile Schistosomes to Praziquantel
| Autor: | Robert M. Greenberg, Lalit Kumar Sharma, Thomas R. Webb, Ravi S. Kasinathan, Charles E. Cunningham |
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| Rok vydání: | 2014 |
| Předmět: |
Tariquidar
ATP-binding cassette transporter Pharmacology Praziquantel 0302 clinical medicine Parasitic Sensitivity Tests Drug Discovery Medicine and Health Sciences Schistosomiasis 0303 health sciences biology lcsh:Public aspects of medicine Drug Resistance Multiple 3. Good health Infectious Diseases Helminth Infections Quinolines Schistosoma RNA Interference Disease Susceptibility Schistosoma mansoni Research Article Neglected Tropical Diseases medicine.drug lcsh:Arctic medicine. Tropical medicine Drug Research and Development lcsh:RC955-962 030231 tropical medicine Xenobiotics 03 medical and health sciences parasitic diseases Parasitic Diseases medicine Animals ATP Binding Cassette Transporter Subfamily B Member 1 Drug Discovery for Neglected Diseases Toxins Biological 030304 developmental biology Parasite Physiology Public Health Environmental and Occupational Health Biology and Life Sciences lcsh:RA1-1270 Transporter Tropical Diseases biology.organism_classification medicine.disease Multiple drug resistance Parasitology |
| Zdroj: | PLoS Neglected Tropical Diseases PLoS Neglected Tropical Diseases, Vol 8, Iss 10, p e3265 (2014) |
| ISSN: | 1935-2735 |
| DOI: | 10.1371/journal.pntd.0003265 |
| Popis: | Parasitic flatworms of the genus Schistosoma cause schistosomiasis, a neglected tropical disease that affects hundreds of millions. Treatment of schistosomiasis depends almost entirely on the drug praziquantel (PZQ). Though essential to treating and controlling schistosomiasis, a major limitation of PZQ is that it is not active against immature mammalian-stage schistosomes. Furthermore, there are reports of field isolates with heritable reductions in PZQ susceptibility, and researchers have selected for PZQ-resistant schistosomes in the laboratory. P-glycoprotein (Pgp; ABCB1) and other ATP binding cassette (ABC) transporters remove a wide variety of toxins and xenobiotics from cells, and have been implicated in multidrug resistance (MDR). Changes in ABC transporter structure or expression levels are also associated with reduced drug susceptibility in parasitic helminths, including schistosomes. Here, we show that the activity of PZQ against schistosome adults and juveniles ex vivo is potentiated by co-administration of either the highly potent Pgp inhibitor tariquidar or combinations of inhibitors targeting multiple ABC multidrug transporters. Adult worms exposed to sublethal PZQ concentrations remain active, but co-administration of ABC transporter inhibitors results in complete loss of motility and disruption of the tegument. Notably, juvenile schistosomes (3–4 weeks post infection), normally refractory to 2 µM PZQ, become paralyzed when transporter inhibitors are added in combination with the PZQ. Experiments using the fluorescent PZQ derivative (R)-PZQ-BODIPY are consistent with the transporter inhibitors increasing effective intraworm concentrations of PZQ. Adult worms in which expression of ABC transporters has been suppressed by RNA interference show increased responsiveness to PZQ and increased retention of (R)-PZQ-BODIPY consistent with an important role for these proteins in setting levels of PZQ susceptibility. These results indicate that parasite ABC multidrug transporters might serve as important targets for enhancing the action of PZQ. They also suggest a potentially novel and readily-available strategy for overcoming reduced PZQ susceptibility of schistosomes. Author Summary Schistosomes are parasitic flatworms that cause schistosomiasis, a tropical disease affecting hundreds of millions worldwide. Praziquantel (PZQ) is the current drug of choice against schistosomiasis, and, indeed, is the only approved antischistosomal treatment available in most parts of the world. Though effective overall, PZQ has limitations, including its lack of activity against immature schistosomes. Furthermore, reported cure rates in the field are often below optimal levels, and there is increasing evidence that schistosomes can become resistant to the drug. ABC transporters such as P-glycoprotein are efflux transporters that mediate detoxification of cells via removal of toxins and xenobiotics, including drugs. They underlie multidrug resistance in mammalian cells, and are also associated with drug resistance in parasitic worms, including schistosomes. Here, we show that compounds that inhibit these efflux transporters potentiate the activity of PZQ against schistosomes, including normally PZQ-insensitive juvenile worms. Similarly, suppressing expression of these transporters also increases adult worm responsiveness to PZQ. Our experiments may provide insights into the role of these drug transporters in PZQ action, and could also translate into new therapeutic strategies for augmenting treatment of schistosome infections and overcoming drug resistance. |
| Databáze: | OpenAIRE |
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