Nicolao, M.C.; Elissondo, M.C.; Denegri, G.M.; Goya, A.B.; Cumino, A.C. "In Vitro and in Vivo effects of tamoxifen against larval stage Echinococcus granulosus" (2014) Antimicrobial Agents and Chemotherapy. 58(9):5146-5154
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Cystic echinococcosis is a zoonotic infection caused by the larval stage of the cestode Echinococcus granulosus. Chemotherapy currently employs benzimidazoles; however, 40% of cases do not respond favorably. With regard to these difficulties, novel therapeutic tools are needed to optimize treatment in humans. The aim of this work was to explore the in vitro and in vivo effects of tamoxifen (TAM) against E. granulosus. In addition, possible mechanisms for the susceptibility of TAM are discussed in relation to calcium homeostasis, P-glycoprotein inhibition, and antagonist effects on a putative steroid receptor. After 24 h of treatment, TAM, at a low micromolar concentration range (10 to 50 μM), inhibited the survival of E. granulosus protoscoleces and metacestodes. Moreover, we demonstrated the chemotherapeutic and chemopreventive pharmacological effects of the drug. At a dose rate of 20 mg/kg of body weight, TAM induced protection against the infection in mice. In the clinical efficacy studies, a reduction in cyst weight was observed after the administration of 20 mg/kg in mice with cysts developed during 3 or 6 months, compared to that of those collected from control mice. Since the collateral effects of high TAM doses have been largely documented in clinical trials, the use of low doses of this drug as a short-term therapy may be a novel alternative approach for human cystic echinococcosis treatment. Copyright © 2014, American Society for Microbiology. All Rights Reserved.


Documento: Artículo
Título:In Vitro and in Vivo effects of tamoxifen against larval stage Echinococcus granulosus
Autor:Nicolao, M.C.; Elissondo, M.C.; Denegri, G.M.; Goya, A.B.; Cumino, A.C.
Filiación:Departamento de Biología, Facultad de Ciencias Exactas Y Naturales, Universidad Nacional de Mar del Plata (UNMdP), Mar del Plata, Argentina
Consejo Nacional de Investigaciones Científicas Y Técnicas (CONICET), Buenos Aires, Argentina
Departamento de Toxinas Marinas, Centro Regional Buenos Aires Sur, Servicio Nacional de Sanidad Y Calidad Agroalimentaria (SENASA), Mar del Plata, Argentina
Departamento de Química, Facultad de Ciencias Exactas Y Naturales, Universidad Nacional de Mar del Plata (UNMdP), Mar del Plata, Argentina
Palabras clave:calcium; multidrug resistance protein; placebo; steroid receptor; tamoxifen citrate; calcium; multidrug resistance protein; steroid receptor; tamoxifen; animal experiment; animal model; anthelmintic activity; article; body weight; calcium homeostasis; chemoprophylaxis; concentration (parameters); controlled study; drug efficacy; echinococcosis; Echinococcus granulosus; female; in vitro study; in vivo study; infection prevention; larval stage; metacestode; mouse; nonhuman; nucleotide sequence; parasite survival; priority journal; weight reduction; animal; antagonists and inhibitors; drug effects; echinococcosis; homeostasis; larva; metabolism; Animals; Calcium; Echinococcosis; Echinococcus granulosus; Female; Homeostasis; Larva; Mice; P-Glycoprotein; Receptors, Steroid; Tamoxifen
Página de inicio:5146
Página de fin:5154
Título revista:Antimicrobial Agents and Chemotherapy
Título revista abreviado:Antimicrob. Agents Chemother.
CAS:calcium, 7440-70-2, 14092-94-5; multidrug resistance protein, 149200-37-3, 208997-77-7; tamoxifen citrate, 54965-24-1; tamoxifen, 10540-29-1; Calcium; P-Glycoprotein; Receptors, Steroid; Tamoxifen


  • Vuitton, D.A., Benzimidazoles for the treatment of cystic and alveolar echinococcosis: What is the consensus? (2009) Expert Rev. Anti Infect. Ther., 7, pp. 145-149. ,
  • Hemphill, A., Stadelmann, B., Scholl, S., Müller, J., Spiliotis, M., Müller, N., Gottstein, B., Siles-Lucas, M., Echinococcus metacestodes as laboratory models for the screening of drugs against cestodes and trematodes (2010) Parasitology, 137, pp. 569-587. ,
  • Naguleswaran, A., Spicher, M., Vonlaufen, N., Ortega-Mora, L.M., Torgerson, P., Gottstein, B., Hemphill, A., In vitro metacestodicidal activities of genistein and other isoflavones against Echinococcus multilocularis and Echinococcus granulosus (2006) Antimicrobial Agents and Chemotherapy, 50 (11), pp. 3770-3778. , DOI 10.1128/AAC.00578-06
  • Spicher, M., Naguleswaran, A., Ortega-Mora, L.M., Müller, J., Gottstein, B., Hemphill, A., In vitro and in vivo effects of 2-methoxyestradiol, either alone or combined with albendazole, against Echinococcus metacestodes (2008) Exp. Parasitol., 119, pp. 475-482. ,
  • Hemer, S., Brehm, K., In vitro efficacy of the anticancer drug imatinib on Echinococcus multilocularis larvae (2012) Int. J. Antimicrob. Agents., 40, pp. 458-462. ,
  • Radmacher, M.D., Simon, R., Estimation of tamoxifen's efficacy for preventing the formation and growth of breast tumors (2000) Journal of the National Cancer Institute, 92 (1), pp. 48-53
  • Mandlekar, S., Hebbar, V., Christov, K., Kong, A., Pharmacodynamics of tamoxifen and its 4-hydroxy and N-desmethyl metabolites: Activation of caspases and induction of apoptosis in rat mammary tumors and in human breast cancer cell lines (2000) Cancer Res., 60, pp. 6601-6606
  • Salami, S., Karami-Tehrani, F., Biochemical studies of apoptosis induced by tamoxifen in estrogen receptor positive and negative breast cancer cell lines (2003) Clinical Biochemistry, 36 (4), pp. 247-253. , DOI 10.1016/S0009-9120(03)00007-9
  • Miguel, D.C., Yokoyama-Yasunaka, J.K.U., Andreoli, W.K., Mortara, R.A., Uliana, S.R.B., Tamoxifen is effective against Leishmania and induces a rapid alkalinization of parasitophorous vacuoles harbouring Leishmania (Leishmania) amazonensis amastigotes (2007) Journal of Antimicrobial Chemotherapy, 60 (3), pp. 526-534. , DOI 10.1093/jac/dkm219
  • Miguel, D.C., Yokoyama-Yasunaka, J.K., Uliana, S.R., Tamoxifen is effective in the treatment of Leishmania amazonensis infections in mice (2008) PLoS Negl. Trop. Dis., 2, pp. e249. ,
  • Miguel, D.C., Ferraz, M.L., Alves, R.D.O., Yokoyama-Yasunaka, J.K., Torrecilhas, A.C., Romanha, A.J., Uliana, S.R., The anticancer drug tamoxifen is active against Trypanosoma cruzi in vitro but ineffective in the treatment of the acute phase of Chagas disease in mice (2010) Mem. Inst. Oswaldo Cruz, 105, pp. 945-948. ,
  • Vargas-Villavicencio, J.A., Larralde, C., De Leon-Nava, M.A., Escobedo, G., Morales-Montor, J., Tamoxifen treatment induces protection in murine cysticercosis (2007) Journal of Parasitology, 93 (6), pp. 1512-1517. , DOI 10.1645/GE-1191.1
  • Escobedo, G., Palacios-Arreola, M.I., Olivos, A., López-Griego, L., Morales-Montor, J., Tamoxifen treatment in hamsters induces protection during taeniosis by Taenia solium (2013) Biomed. Res. Int., 2013, p. 280496. ,
  • Shiau, A.K., Barstad, D., Loria, P.M., Cheng, L., Kushner, P.J., Agard, D.A., Greene, G.L., The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen (1998) Cell, 95 (7), pp. 927-937. , DOI 10.1016/S0092-8674(00)81717-1
  • Paulmurugan, R., Gambhir, S.S., An intramolecular folding sensor for imaging estrogen receptor-ligand interactions (2006) Proceedings of the National Academy of Sciences of the United States of America, 103 (43), pp. 15883-15888. , DOI 10.1073/pnas.0607385103
  • Maximov, P.Y., Myers, C.B., Curpan, R.F., Lewis-Wambi, J.S., Jordan, V.C., Structure-function relationships of estrogenic triphenylethylenes related to endoxifen and 4-hydroxytamoxifen (2010) J. Med. Chem., 53, pp. 3273-3283. ,
  • Förster, S., Günthel, D., Kiss, F., Brehm, K., Molecular characterisation of a serum-responsive, DAF-12-like nuclear hormone receptor of the foxtapeworm Echinococcus multilocularis (2011) J. Cell Biochem., 112, pp. 1630-1642. ,
  • Dolan, K., Montgomery, S., Buchheit, B., Didone, L., Wellington, M., Krysan, D.J., Antifungal activity of tamoxifen: In vitro and in vivo activities and mechanistic characterization (2009) Antimicrob. Agents Chemother., 53, pp. 3337-3346. ,
  • Friedman, Z.Y., Recent advance in the molecular mechanisms of tamoxifen action (1998) Cancer Invest., 16, pp. 391-396. ,
  • Cumino, A.C., Lamenza, P., Denegri, G.M., Identification of functional FKB protein in Echinococcus granulosus: Its involvement in the protoscolicidal action of rapamycin derivates and in calcium homeostasis (2010) Int. J. Parasitol., 40, pp. 651-661. ,
  • Elissondo, M.C., Ceballos, L., Alvarez, L., Sánchez Bruni, S., Lanusse, C., Denegri, G., Flubendazole and ivermectin in vitro combination therapy produces a marked effect on Echinococcus granulosus protoscoleces and metacestodes (2009) Parasitol. Res., 105, pp. 835-842. ,
  • Nicolao, M.C., Denegri, G.M., Cárcamo, J.G., Cumino, A.C., P-glycoprotein expression and pharmacological modulation in larval stages of Echinococcus granulosus (2014) Parasitol. Int., 63, pp. 1-8. ,
  • Cumino, A.C., Nicolao, M.C., Loos, J.A., Denegri, G., Elissondo, M.C., Echinococcus granulosus tegumental enzymes as in vitro markers of pharmacological damage: A biochemical and molecular approach (2012) Parasitol. Int., 61, pp. 579-585. ,
  • Jordan, V.C., Bain, R.R., Brown, R.R., Determination and pharmacology of a new hydroxylated metabolite of tamoxifen observed in patient sera during therapy for advanced breast cancer (1983) Cancer Research, 43 (3), pp. 1446-1450
  • Urrea-París, M.A., Moreno, M.J., Casado, N., Rodriguez-Caabeiro, F., In vitro effect of praziquantel and albendazole combination therapy on the larval stage of Echinococcus granulosus (2000) Parasitol. Res., 86, pp. 957-964. ,
  • Casado, N., Urrea-Paris, M., Moreno, M., Rodriguez-Caabeiro, F., Combined praziquantel and albendazole chemoprophylaxis in experimental hydatidosis (2001) Parasitology Research, 87 (9), pp. 787-789. , DOI 10.1007/s004360100443
  • Ceballos, L., Elissondo, C., Confalonieri, A., Denegri, G., Alvarez, L., Lanusse, C., Chemoprophylactic activity of flubendazole in cystic echinococcosis (2010) Chemotherapy, 56, pp. 386-392. ,
  • Urrea-Paris, M., Moreno, M., Casado, N., Rodriguez-Caabeiro, F., Relationship between the efficacy of praziquantel treatment and the cystic differentiation in vivo of Echinococcus granulosus metacestode (2002) Parasitology Research, 88 (1), pp. 26-31
  • Ceballos, L., Elissondo, C., Moreno, L., Dopchiz, M., Bruni, S.S., Denegri, G., Alvarez, L., Lanusse, C., Albendazole treatment in cystic echinococcosis: Pharmacokinetics and clinical efficacy of two different aqueous formulations (2008) Parasitol. Res., 103, pp. 355-362. ,
  • Ceballos, L., Elissondo, M., Bruni, S.S., Denegri, G., Alvarez, L., Lanusse, C., Flubendazole in cystic echinococcosis therapy: Pharmaco-parasitological evaluation in mice (2009) Parasitol. Int., 58, pp. 354-358. ,
  • Kisanga, E.R., Gjerde, J., Guerrieri-Gonzaga, A., Pigatto, F., Pesci-Feltri, A., Robertson, C., Serrano, D., Lien, E.A., Tamoxifen and Metabolite Concentrations in Serum and Breast Cancer Tissue during Three Dose Regimens in a Randomized Preoperative Trial (2004) Clinical Cancer Research, 10 (7), pp. 2336-2343. , DOI 10.1158/1078-0432.CCR-03-0538
  • Callaghan, R., Higgins, C.F., Interaction of tamoxifen with the multidrug resistance P-glycoprotein (1995) Br. J. Cancer, 71, pp. 294-299. ,
  • Hennessy, M., Spiers, J.P., A primer on the mechanics of P-glycoprotein the multidrug transporter (2007) Pharmacological Research, 55 (1), pp. 1-15. , DOI 10.1016/j.phrs.2006.10.007, PII S1043661806001897
  • Robinson, S.P., Langan-Fahey, S.M., Johnson, D.A., Jordan, C.V., Metabolites, pharmacodynamics, and pharmacokinetics of tamoxifen in rats and mice compared to the breast cancer patient (1991) Drug Metab. Dispos., 19, pp. 36-43
  • Wollam, J., Antebi, A., Sterol regulation of metabolism, homeostasis, and development (2011) Annu. Rev. Biochem., 80, pp. 885-916. ,
  • Hernández-Bello, R., Escobedo, G., Guzman, C., Ibarra-Coronado, E.G., López-Griego, L., Morales-Montor, J., Immunoendocrine hostparasite interactions during helminth infections: From the basic knowledge to its possible therapeutic applications (2010) Parasite Immunol., 32, pp. 633-643. ,
  • Eick, G.N., Colucci, J.K., Harms, M.J., Ortlund, E.A., Thornton, J.W., Evolution of minimal specificity and promiscuity in steroid hormone receptors (2012) PLoS Genet., 8, pp. e1003072. ,
  • Obal, G., Ramos, A.L., Silva, V., Lima, A., Batthyany, C., Bessio, M.I., Ferreira, F., Ferreira, A.M., Characterisation of the native lipid moiety of Echinococcus granulosus antigen B (2012) PLoS Negl. Trop. Dis., 6, pp. e1642. ,
  • Li, L., Li, Z., Sacks, D.B., The transcriptional activity of estrogen receptor is dependent on Ca2/calmodulin (2005) J. Biol. Chem., 280, pp. 13097-13104. ,
  • Zhang, Y., Li, Z., Sacks, D.B., Ames, J.B., Structural basis for Ca2+-induced activation and dimerization of estrogen receptor α by calmodulin (2012) J. Biol. Chem., 287, pp. 9336-9344. ,
  • Parsons, A.B., Lopez, A., Givoni, I.E., Williams, D.E., Gray, C.A., Porter, J., Chua, G., Boone, C., Exploring the Mode-of-Action of Bioactive Compounds by Chemical-Genetic Profiling in Yeast (2006) Cell, 126 (3), pp. 611-625. , DOI 10.1016/j.cell.2006.06.040, PII S0092867406009068


---------- APA ----------
Nicolao, M.C., Elissondo, M.C., Denegri, G.M., Goya, A.B. & Cumino, A.C. (2014) . In Vitro and in Vivo effects of tamoxifen against larval stage Echinococcus granulosus. Antimicrobial Agents and Chemotherapy, 58(9), 5146-5154.
---------- CHICAGO ----------
Nicolao, M.C., Elissondo, M.C., Denegri, G.M., Goya, A.B., Cumino, A.C. "In Vitro and in Vivo effects of tamoxifen against larval stage Echinococcus granulosus" . Antimicrobial Agents and Chemotherapy 58, no. 9 (2014) : 5146-5154.
---------- MLA ----------
Nicolao, M.C., Elissondo, M.C., Denegri, G.M., Goya, A.B., Cumino, A.C. "In Vitro and in Vivo effects of tamoxifen against larval stage Echinococcus granulosus" . Antimicrobial Agents and Chemotherapy, vol. 58, no. 9, 2014, pp. 5146-5154.
---------- VANCOUVER ----------
Nicolao, M.C., Elissondo, M.C., Denegri, G.M., Goya, A.B., Cumino, A.C. In Vitro and in Vivo effects of tamoxifen against larval stage Echinococcus granulosus. Antimicrob. Agents Chemother. 2014;58(9):5146-5154.