P-glycoprotein efflux pump plays an important role in Trypanosoma cruzi drug resistance

• Published in: Parasitology research (1987) 2013-06, Vol.112 (6), p.2341-2351
• Main Authors: Campos, Mônica Caroline Oliveira, Castro-Pinto, Denise Barçante, Ribeiro, Grazielle Alves, Berredo-Pinho, Márcia Moreira, Gomes, Leonardo Henrique Ferreira, da Silva Bellieny, Myrtes Santos, Goulart, Carla Marins, Echevarria, Áurea, Leon, Leonor Laura
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphatases; Adenosine Triphosphatases - genetics; Adenosine Triphosphatases - metabolism; adenosinetriphosphatase; amastigotes; Antiprotozoal Agents; Antiprotozoal Agents - metabolism; Antiprotozoal Agents - pharmacology; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; Biomedical and Life Sciences; Biomedicine; cross resistance; drug effects; Drug Resistance; Drug resistance in microorganisms; epimastigotes; Gene Expression Profiling; gene overexpression; genes; genetics; Glycoproteins; Health aspects; Immunology; induced resistance; Medical Microbiology; metabolism; Microbiology; Nitroimidazoles; Nitroimidazoles - metabolism; Nitroimidazoles - pharmacology; Original Paper; parasites; pharmacology; phenotype; Physiological aspects; Protozoan Proteins; Protozoan Proteins - metabolism; Thiosemicarbazones; Thiosemicarbazones - metabolism; Thiosemicarbazones - pharmacology; transporters; Trypanosoma cruzi; Trypanosoma cruzi - drug effects; Trypanosoma cruzi - genetics; Trypanosoma cruzi - metabolism; trypomastigotes
• ISSN: 0932-0113; 1432-1955; 1432-1955
• DOI: 10.1007/s00436-013-3398-z

Drug resistance in protozoan parasites has been associated with the P-glycoprotein (Pgp), an energy-dependent efflux pump that transports substances across the membrane. Interestingly, the genes TcPGP1 and TcPGP2 have been described in Trypanosoma cruzi , although the function of these genes has not been fully elucidated. The main goal of this work was to investigate Pgp efflux pump activity and expression in T. cruzi lines submitted to in vitro induced resistance to the compounds 4- N -(2-methoxy styryl)-thiosemicarbazone (2-Meotio) and benznidazole (Bz) and to verify the stability of the resistant phenotypes during the parasite life cycle. We observed that the EC 50 values for the treatment of epimastigotes with 2-Meotio or Bz were increased at least 4.7-fold in resistant lines, and this phenotype was maintained in metacyclic trypomastigotes, cell-derived trypomastigotes, and intracellular amastigotes. However, in epimastigotes, 2-Meotio resistance is reversible, but Bz resistance is irreversible. When compared with the parental line, the resistant lines exhibited higher Pgp efflux activity, reversion of the resistant phenotypes in the presence of Pgp inhibitors, cross-resistance with Pgp modulators, higher basal Pgp ATPase activity, and overexpression of the genes TcPGP1 and TcPGP2 . In conclusion, the resistance induced in T. cruzi by the compounds 2-Meotio and Bz is maintained during the entire parasite life cycle. Furthermore, our data suggest the participation of the Pgp efflux pump in T. cruzi drug resistance.