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Tamoxifen in the treatment of leishmaniasis: evaluation of efficacy in combination therapy schemes and study of the antileishmanial mechanism of action

Grant number: 11/20484-7
Support type:Regular Research Grants
Duration: March 01, 2012 - August 31, 2014
Field of knowledge:Biological Sciences - Parasitology - Protozoology of Parasites
Principal Investigator:Silvia Reni Bortolin Uliana
Grantee:Silvia Reni Bortolin Uliana
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated grant(s):12/51018-4 - New approaches to combination chemotherapy for human leishmaniasis, AP.R

Abstract

The treatment of all clinical forms of leishmaniasis relies on costly parenteral administered drugs with multiple undesirable effects. We have recently described the antileishmanial activity of tamoxifen, a drug already in use for the treatment of breast cancer for over 30 years. Tamoxifen has been shown to be effective in several in vivo experimental models of visceral and cutaneous leishmaniasis. A new clinical use of tamoxifen would be much strengthened by the characterization of its activity in combination therapy, as to the efficacy and undesirable effects. To progress in the understanding and characterization of this new alternative for leishmaniasis chemotherapy we aim at: evaluating the efficacy of tamoxifen when used in combination with meglumine antimoniate, amphotericin B or miltefosine in vitro and in vivo; testing the effectiveness of tamoxifen in experimental models of cutaneous leishmaniasis when applied topically, alone and in combination with the classical antileishmanial agents; determining the activity of a library of molecules structurally related to estrogen receptor modulators against the parasite in vitro, searching for more active and specific drugs; studying the metabolism of sphingolipids in tamoxifen treated promastigotes, aiming at defining possible molecular targets of its antileishmanial activity. (AU)

Scientific publications (13)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
ESPADA, CAROLINE R.; MAGALHAES, RUBENS M.; CRUZ, MARIO C.; MACHADO, PAULO R.; SCHRIEFER, ALBERT; CARVALHO, EDGAR M.; HORNILLOS, VALENTIN; ALVES, JOAO M.; CRUZ, ANGELA K.; COELHO, ADRIANO C.; ULIANA, SILVIA R. B. Investigation of the pathways related to intrinsic miltefosine tolerance in Leishmania (Viannia) braziliensis clinical isolates reveals differences in drug uptake. INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE, v. 11, n. SI, p. 139-147, DEC 2019. Web of Science Citations: 0.
ESPADA, CAROLINE R.; ORTIZ, PAOLA A.; SHAW, JEFFREY J.; BARRAL, ALDINA M. P.; COSTA, JACKSON M. L.; ULIANA, SILVIA R. B.; COELHO, ADRIANO C. Identification of Leishmania (Viannia) species and clinical isolates of Leishmania (Leishmania) amazonensis from Brazil using PCR-RFLP of the heat-shock protein 70 gene reveals some unexpected observations. DIAGNOSTIC MICROBIOLOGY AND INFECTIOUS DISEASE, v. 91, n. 4, p. 312-318, AUG 2018. Web of Science Citations: 7.
TRINCONI, CRISTIANA T.; REIMAO, JULIANA Q.; BONANO, I, VIVIAN; ESPADA, CAROLINE R.; MIGUEL, DANILO C.; YOKOYAMA-YASUNAKA, JENICER K. U.; ULIANA, SILVIA R. B. Topical tamoxifen in the therapy of cutaneous leishmaniasis. Parasitology, v. 145, n. 4, SI, p. 490-496, APR 2018. Web of Science Citations: 10.
ESPADA, CAROLINE R.; RIBEIRO-DIAS, FATIMA; DORTA, MIRIAM L.; DE ARAUJO PEREIRA, LEDICE INACIA; DE CARVALHO, EDGAR M.; MACHADO, PAULO R.; SCHRIEFER, ALBERT; YOKOYAMA-YASUNAKA, JENICER K. U.; COELHO, ADRIANO C.; ULIANA, SILVIA R. B. Susceptibility to Miltefosine in Brazilian Clinical Isolates of Leishmania (Viannia) braziliensis. American Journal of Tropical Medicine and Hygiene, v. 96, n. 3, p. 656-659, 2017. Web of Science Citations: 2.
COELHO, ADRIANO C.; OLIVEIRA, JORDANA C.; ESPADA, CAROLINE R.; REIMAO, JULIANA Q.; TRINCONI, CRISTIANA T.; ULIANA, SILVIA R. B. A Luciferase-Expressing Leishmania braziliensis Line That Leads to Sustained Skin Lesions in BALB/c Mice and Allows Monitoring of Miltefosine Treatment Outcome. PLoS Neglected Tropical Diseases, v. 10, n. 5 MAY 2016. Web of Science Citations: 4.
TRINCONI, CRISTIANA T.; REIMAO, JULIANA Q.; COELHO, ADRIANO C.; ULIANA, SILVIA R. B. Efficacy of tamoxifen and miltefosine combined therapy for cutaneous leishmaniasis in the murine model of infection with Leishmania amazonensis. Journal of Antimicrobial Chemotherapy, v. 71, n. 5, p. 1314-1322, MAY 2016. Web of Science Citations: 14.
COELHO, ADRIANO C.; TRINCONI, CRISTIANA T.; SENRA, LUISA; YOKOYAMA-YASUNAKA, JENICER K. U.; ULIANA, SILVIA R. B. Leishmania is not prone to develop resistance to tamoxifen. INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE, v. 5, n. 3, p. 77-83, DEC 2015. Web of Science Citations: 9.
REIMAO, JULIANA Q.; OLIVEIRA, JORDANA C.; TRINCONI, CRISTIANA T.; COTRIM, PAULO C.; COELHO, ADRIANO C.; ULIANA, SILVIA R. B. Generation of Luciferase-Expressing Leishmania infantum chagasi and Assessment of Miltefosine Efficacy in Infected Hamsters through Bioimaging. PLoS Neglected Tropical Diseases, v. 9, n. 2 FEB 2015. Web of Science Citations: 11.
COELHO, ADRIANO C.; TRINCONI, CRISTIANA T.; COSTA, CARLOS H. N.; ULIANA, SILVIA R. B. In Vitro and In Vivo Miltefosine Susceptibility of a Leishmania amazonensis Isolate from a Patient with Diffuse Cutaneous Leishmaniasis. PLoS Neglected Tropical Diseases, v. 8, n. 7 JUL 2014. Web of Science Citations: 18.
REIMAO, JULIANA Q.; MIGUEL, DANILO C.; TANIWAKI, NOEMI N.; TRINCONI, CRISTIANA T.; YOKOYAMA-YASUNAKA, JENICER K. U.; ULIANA, SILVIA R. B. Antileishmanial Activity of the Estrogen Receptor Modulator Raloxifene. PLoS Neglected Tropical Diseases, v. 8, n. 5 MAY 2014. Web of Science Citations: 13.
TRINCONI, CRISTIANA T.; REIMAO, JULIANA Q.; YOKOYAMA-YASUNAKA, JENICER K. U.; MIGUEL, DANILO C.; ULIANA, SILVIA R. B. Combination Therapy with Tamoxifen and Amphotericin B in Experimental Cutaneous Leishmaniasis. Antimicrobial Agents and Chemotherapy, v. 58, n. 5, p. 2608-2613, MAY 2014. Web of Science Citations: 24.
BONANO, VIVIAN I.; YOKOYAMA-YASUNAKA, JENICER K. U.; MIGUEL, DANILO C.; JONES, SCOTT A.; DODGE, JEFFREY A.; ULIANA, SILVIA R. B. Discovery of Synthetic Leishmania Inhibitors by Screening of a 2-Arylbenzothiophene Library. CHEMICAL BIOLOGY & DRUG DESIGN, v. 83, n. 3, p. 289-296, MAR 2014. Web of Science Citations: 7.
REIMAO, JULIANA Q.; TRINCONI, CRISTIANA T.; YOKOYAMA-YASUNAKA, JENICER K.; MIGUEL, DANILO C.; KALIL, SANDRA P.; ULIANA, SILVIA R. B. Parasite burden in Leishmania (Leishmania) amazonensis-infected mice: Validation of luciferase as a quantitative tool. Journal of Microbiological Methods, v. 93, n. 2, p. 95-101, MAY 2013. Web of Science Citations: 23.

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