TAMOXIFEN AS AN ANTI-LEISHMANIAL DRUG: ACTIVITY IN COMBINED THERAPEUTIC SCHEMES AND STUDY OF THE MECHANISM OF ACTION

• Grant number: 11/18858-6
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: February 01, 2012
• End date: October 31, 2015
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: Silvia Reni Bortolin Uliana
• Grantee: Cristiana de Melo Trinconi Tronco
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Leishmaniasis is a disease with a wide clinical spectrum caused by more than 20 species of protozoa of the genus Leishmania. The disease is distributed worldwide and its incidence has increased considerably in recent decades. Current treatment schemes present many problems with responses that are often unpredictable and unsatisfactory. In addition, some strains of Leishmania have shown resistance to classical drugs, leading many authors to propose the use of combination therapies. Studies in our laboratory demonstrated the leishmanicidal activity of the anticancer compound tamoxifen. We found that this drug is active against several species of Leishmania in vitro and in vivo both by parenteral and topical routes. We also observed that tamoxifen causes changes in the biosynthesis of sphingolipids in Leishmania. The main changes observed are related to the synthesis of ceramide, acylated ceramide, glucosylceramide and inositolphosphorylceramide. Consequently, the objectives of this project are: i) to evaluate the effectiveness of tamoxifen in combination with drugs currently used in the therapy of leishmaniasis in vitro and in vivo, and ii) to characterize the effect of tamoxifen on the biosynthesis of sphingolipids in Leishmania, with particular focus on the activity of ceramidase and glucosylceramide synthase, as well as in the de novo synthesis of inositol and its transport in treated cells.

Scientific publications

(10)

(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)

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. (15/05130-5, 11/18858-6, 15/09080-2, 11/20484-7, 11/21970-2)

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. (15/05130-5, 11/18858-6, 12/14629-5, 15/09080-2, 11/20484-7)

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. (11/20484-7, 12/14629-5, 11/18858-6)

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. (11/20484-7, 11/18858-6)

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. (11/20484-7, 11/18858-6, 11/21970-2)

TRINCONI, CRISTIANA T.; MIGUEL, DANILO C.; SILBER, ARIEL M.; BROWN, CHRISTOPHER; MINA, JOHN G. M.; DENNY, PAUL W.; HEISE, NORTON; ULIANA, SILVIA R. B.. Tamoxifen inhibits the biosynthesis of inositolphosphorylceramide in Leishmania. INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE, v. 8, n. 3, p. 475-487, DEC 2018. (15/09080-2, 11/18858-6)

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. (11/20484-7, 12/14629-5, 11/18858-6)

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. (11/18858-6, 12/14629-5, 15/09080-2, 11/20484-7, 11/21970-2)

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. (11/20484-7, 11/18858-6, 13/01613-6, 11/21970-2)

TRINCONI, CRISTIANA T.; REIMAO, JULIANA Q.; BONANO, VIVIAN, I; 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, p. 7-pg., 2018-04-01. (11/18858-6, 15/09080-2, 11/21970-2, 11/20484-7, 15/05130-5)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

TRONCO, Cristiana de Melo Trinconi. Tamoxifen in leishmaniasis treatment: activity in combined therapeutic schemes and study of mechanism of action.. 2015. Doctoral Thesis - Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI) São Paulo.