Cyclosporin A inhibits calcineurin (phosphatase 2B) and P-glycoprotein activity in Entamoeba histolytica.
Cyclosporin A (CsA) inhibits the proliferation of several protozoan parasites through blocking the activity of calcineurin (Cn) or P-glycoproteins (Pgp). We report here, that inhibition of the proliferation of Entamoeba histolytica trophozoites, the causal agent of human amebiasis, is due to interference of the phosphatase activity of Cn, in a similar fashion to the effect of this immunosuppressive drug on T lymphocytes. The non-immunosuppressive CsA analog PSC-833, which binds Pgp without interfering the function of Cn, did not inhibit the proliferation of HM1:IMSS trophozoites. Moreover, phosphatase activity of amebic Cn, detected using the phosphopeptide RII, was drastically affected by incubation with CsA, but not with PSC-833. On the other hand, both drugs were also tested on clone C2 trophozoites, which grow in the presence of emetine due to over-expression of Pgp. The effect of CsA was similar to that observed on HM1:IMSS trophozoites, whereas PSC-833 only affected the proliferation and viability of clone C2 when the trophozoites were grown in the presence of 40 microM of emetine, suggesting an interference of the Pgp activity. This suggestion was confirmed by results from experiments of Pgp-dependent effux of rhodamine from pre-loaded trophozoites, in the presence of either of these drugs. Therefore, CsA inhibition of E. histolytica trophozoite proliferation is more likely due to Cn than Pgp activity inhibition.
Carrero
Julio C
JC
Departamento de Inmunología, Instituto de Investigaciones Biomédicas, UNAM, A.P. 70228, 04510 México DF, Mexico. carrero@servidor.unam.mx
Lugo
Haydee
H
Pérez
D Guillermo
DG
Ortiz-Martínez
César
C
Laclette
Juan P
JP
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004748:Entamoeba histolytica / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D012235:Rhodamines / Q000493:pharmacokinetics; D016559:Tacrolimus / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000981:Antiprotozoal Agents; D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D012235:Rhodamines; D016572:Cyclosporine; D019703:Calcineurin; D010744:Phosphoric Monoester Hydrolases; D016559:Tacrolimus