title: The Role of Efflux Pumps in Schistosoma mansoni Praziquantel Resistant Phenotype.
abstract: BACKGROUND
  Schistosomiasis is a neglected disease caused by a trematode of the genus Schistosoma that is second only to malaria in public health significance in Africa, South America, and Asia. Praziquantel (PZQ) is the drug of choice to treat this disease due to its high cure rates and no significant side effects. However, in the last years increasingly cases of tolerance to PZQ have been reported, which has caused growing concerns regarding the emergency of resistance to this drug.
  
  
  RESULTS
  Here we describe the selection of a parasitic strain that has a stable resistance phenotype to PZQ. It has been reported that drug resistance in helminths might involve efflux pumps such as members of ATP-binding cassette transport proteins, including P-glycoprotein and multidrug resistance-associated protein families. Here we evaluate the role of efflux pumps in Schistosoma mansoni resistance to PZQ, by comparing the efflux pumps activity in susceptible and resistant strains. The evaluation of the efflux activity was performed by an ethidium bromide accumulation assay in presence and absence of Verapamil. The role of efflux pumps in resistance to PZQ was further investigated comparing the response of susceptible and resistant parasites in the absence and presence of different doses of Verapamil, in an ex vivo assay, and these results were further reinforced through the comparison of the expression levels of SmMDR2 RNA by RT-PCR.
  
  
  CONCLUSIONS
  This work strongly suggests the involvement of Pgp-like transporters SMDR2 in Praziquantel drug resistance in S. mansoni. Low doses of Verapamil successfully reverted drug resistance. Our results might give an indication that a combination therapy with PZQ and natural or synthetic Pgp modulators can be an effective strategy for the treatment of confirmed cases of resistance to PZQ in S. mansoni.
authors.affiliation: Graduate Program in Areas of Basic and Applied Biology, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal; Medical Parasitology Unit, Global Health and Tropical Medicine, GHTM, Instituto de Higiene e Medicina Tropical, IHMT, Universidade Nova de Lisboa, UNL, Lisbon, Portugal; Universidade de São Paulo, Instituto de Química de São Carlos, São Carlos, SP, Brazil.
authors.forename: António
authors.initials: A
authors.lastname: Pinto-Almeida
authors.affiliation: Medical Parasitology Unit, Global Health and Tropical Medicine, GHTM, Instituto de Higiene e Medicina Tropical, IHMT, Universidade Nova de Lisboa, UNL, Lisbon, Portugal; Institute of Biology, Universidade de Campinas, Campinas, SP, Brazil.
authors.forename: Tiago
authors.initials: T
authors.lastname: Mendes
authors.affiliation: Medical Microbiology Unit, Global Health and Tropical Medicine, GHTM, Instituto de Higiene e Medicina Tropical, IHMT, Universidade Nova de Lisboa, UNL, Lisbon, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Armada
authors.affiliation: Medical Parasitology Unit, Global Health and Tropical Medicine, GHTM, Instituto de Higiene e Medicina Tropical, IHMT, Universidade Nova de Lisboa, UNL, Lisbon, Portugal.
authors.forename: Silvana
authors.initials: S
authors.lastname: Belo
authors.affiliation: Universidade de São Paulo, Instituto de Química de São Carlos, São Carlos, SP, Brazil.
authors.forename: Emanuel
authors.initials: E
authors.lastname: Carrilho
authors.affiliation: Medical Microbiology Unit, Global Health and Tropical Medicine, GHTM, Instituto de Higiene e Medicina Tropical, IHMT, Universidade Nova de Lisboa, UNL, Lisbon, Portugal.
authors.forename: Miguel
authors.initials: M
authors.lastname: Viveiros
authors.affiliation: Medical Parasitology Unit, Global Health and Tropical Medicine, GHTM, Instituto de Higiene e Medicina Tropical, IHMT, Universidade Nova de Lisboa, UNL, Lisbon, Portugal; Universidade de São Paulo, Instituto de Química de São Carlos, São Carlos, SP, Brazil; Laboratory of Parasitology, Departamento de Morfologia e Patologia, Universidade Federal de São Carlos, São Carlos, SP, Brazil.
authors.forename: Ana
authors.initials: A
authors.lastname: Afonso
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology*; D004351:Drug Resistance; D015801:Helminth Proteins / Q000235:genetics; D008297:Male; D051379:Mice; D010641:Phenotype; D011223:Praziquantel / Q000494:pharmacology*; D012550:Schistosoma mansoni / Q000187:drug effects* / Q000235:genetics*; D012555:Schistosomiasis mansoni / Q000188:drug therapy* / Q000469:parasitology*; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D000871:Anthelmintics; D015801:Helminth Proteins; D011223:Praziquantel; D000097202:ATP-Binding Cassette Sub-Family B Member 4