| The pharmacological inhibition of sterol biosynthesis in Leishmania is counteracted by enhancement of LDL endocytosis. | |
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MedLine Citation:
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PMID: 21601554 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Leishmania parasites, despite being able to synthesize their own sterols, acquire and accumulate significant amounts of cholesterol through low density lipoprotein (LDL) particle endocytosis. The role of this system in Leishmania amazonensis promastigotes under pharmacological pressure by sterol biosynthesis inhibitors (SBIs) was investigated. First, thin layer chromatography demonstrated that L. amazonensis promastigotes, in response to ergosterol biosynthesis inhibition by treatment with 4.0 and 6.0μM ketoconazole or miconazole, accumulate up to two times more cholesterol than controls. The treatment of promastigotes with ketoconazole and simvastatin, two SBIs with non-related mechanisms of action, showed that both drugs induce increases in (125)I-LDL endocytosis in a dose-dependent manner, indicating that the accumulation of exogenous cholesterol is due to the enhancement of LDL uptake. Finally, it was demonstrated that L. amazonensis promastigotes were rendered more susceptible to treatment with SBIs (ketoconazole, miconazole, simvastatin and terbinafine) in the absence of exogenous cholesterol sources, with a reduction of the IC50s of about 50% in three of the four tested drugs. These results show that the exogenous cholesterol uptake system in L. amazonensis plays a role as a compensatory mechanism in response to the presence of SBIs, suggesting that it may be a potential pharmacological target. |
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Authors:
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Valter Viana de Andrade-Neto; Nuccia Nicole Theodore Cicco; Edézio Ferreira da Cunha-Junior; Marilene Marcuzzo do Canto-Cavalheiro; Georgia Correa Atella; Eduardo Caio Torres-Santos |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-5-13 |
Journal Detail:
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Title: Acta tropica Volume: - ISSN: 1873-6254 ISO Abbreviation: - Publication Date: 2011 May |
Date Detail:
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Created Date: 2011-5-23 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0370374 Medline TA: Acta Trop Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2011. Published by Elsevier B.V. |
Affiliation:
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Laboratório de Bioquímica de Tripanosomatídeos, Instituto Oswaldo Cruz, FIOCRUZ, Av Brasil, 4365, Manguinhos, Rio de Janeiro 21040-900, RJ, Brazil. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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