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Doctoral Thesis
DOI
10.11606/T.42.2016.tde-19042016-171456
Document
Author
Full name
Cristiana de Melo Trinconi Tronco
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2015
Supervisor
Committee
Uliana, Silvia Reni Bortolin (President)
Bergmann, Bartira Rossi
Frezard, Frederic Jean Georges
Katzin, Alejandro Miguel
Shaw, Jeffrey Jon
Title in Portuguese
Tamoxifeno no tratamento de leishmaniose: atividade em esquemas terapéuticos combinados e estudo do mecanismo de ação.
Keywords in Portuguese
Leishmania
Ceramida acilada
Esfingolipídios
Inositol
IPC
PI
Quimioterapia
Tamoxifeno
Terapia combinada
Abstract in Portuguese
A leishmaniose é uma doença parasitária de ampla distribuição, para a qual se dispõe de um limitado arsenal terapêutico. Trabalhos recentes mostraram que tamoxifeno é eficaz no tratamento de leishmaniose experimental. Nesse trabalho, avaliamos a terapia combinada de tamoxifeno com os fármacos utilizados atualmente no tratamento desta enfermidade. A interação entre os fármacos mostrou-se aditiva, tanto in vitro como in vivo. Em paralelo, analisamos os efeitos de tamoxifeno na biossíntese de esfingolipídios em Leishmania, sendo identificada a redução da síntese de fosfatidilinositol e inositolfosforil ceramida (IPC) e acúmulo de ceramida acilada. A redução na biossíntese de IPC não pode ser atribuída a redução no transporte de inositol, mas provavelmente está relacionada à inibição da enzima IPC sintase. Estes resultados indicam novas estratégias para superar as deficiências encontradas no tratamento de leishmaniose utilizando tamoxifeno, um fármaco clinicamente bem conhecido que exerce ações em múltiplos alvos em Leishmania.
Title in English
Tamoxifen in leishmaniasis treatment: activity in combined therapeutic schemes and study of mechanism of action.
Keywords in English
Leishmania
Acil ceramide
Chemotherapy
Combined therapy
Inositol
IPC
PI
Sphingolipids
Tamoxifen
Abstract in English
Leishmaniasis is a parasitic disease with wide distribution and limited treatment. Recent reports demonstrate that tamoxifen is an effective drug for experimental leishmaniasis treatment. In this work, we evaluated the combined therapy of tamoxifen with current drugs used in leishmaniasis chemotherapy. The drug interaction was additive both, in vitro and in vivo. We also evaluated tamoxifen effect on in Leishmania sphingolipids biosynthesis. We found a reduction in phosphatidylinositol and inositol phosphorylceramide (IPC) synthesis and an accumulation of acilceramide. The reduction in IPC biosynthesis could not be assigned to the reduction observed in inositol transport, but probably is related to IPC synthase inhibition. These results show new strategies to circumvent shortcomings of leishmaniasis treatment using tamoxifen, a multitarget drug in Leishmania and widely used in the chemotherapy of breast cancer.
 
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Release Date
2018-05-10
Publishing Date
2016-05-10
 
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