TY - JOUR
T1 - Cyclosporin A inhibits calcineurin (phosphatase 2B) and P-glycoprotein activity in Entamoeba histolytica
AU - Carrero, Julio C.
AU - Lugo, Haydee
AU - Pérez, D. Guillermo
AU - Ortiz-Martínez, César
AU - Laclette, Juan P.
N1 - Funding Information:
PSC-833 was kindly provided by Novartis Pharma AG, Basel, Switzerland. We thank A. Olivos, B. Sánchez-Hernández and M. Nequiz for supplying HM1:IMSS trophozoites and technical assistance. This work was partially supported by research Grants from CONACYT (41693-M: J.P.L. and J.C.C.; J34137-M: D.G.P.), DGAPA UNAM (IN206102-3: J.P.L. and J.C.C), CGPI (20030922: D.G.P.) and Fundación Miguel Alemán, A.C. (JPL).
PY - 2004/8
Y1 - 2004/8
N2 - 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 μM 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.
AB - 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 μM 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.
KW - Calcineurin
KW - Cyclosporin A
KW - Entamoeba histolytica
KW - Immunosuppressor
KW - P-glycoprotein
KW - PSC-833
UR - http://www.scopus.com/inward/record.url?scp=4143049147&partnerID=8YFLogxK
U2 - 10.1016/j.ijpara.2004.05.004
DO - 10.1016/j.ijpara.2004.05.004
M3 - Artículo
C2 - 15313136
SN - 0020-7519
VL - 34
SP - 1091
EP - 1097
JO - International Journal for Parasitology
JF - International Journal for Parasitology
IS - 9
ER -