| The farnesyl transferase inhibitors Tipifarnib and Lonafarnib inhibit cytokines secretion in a cellular model of mevalonate kinase deficiency. | |
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MedLine Citation:
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PMID: 21430599 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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The shortage of geranylgeranylpyrophosphate (GGPP) was associated to an increased IL-1β release in the auto-inflammatory syndrome mevalonate kinase deficiency (MKD), a rare inherited disease that has no specific therapy. Farnesyl-transferase inhibitors (FTIs) act at the end of mevalonate pathway. Two FTIs, Tipifarnib and Lonafarnib, were therefore evaluated as possible therapeutical choices for the treatment of MKD. FTIs could lead to a redirection of the limited available number of mevalonate intermediates preferentially to GGPP synthesis, eventually preventing the uncontrolled inflammatory response. The effect of Tipifarnib and Lonafarnib on intracellular cholesterol level (ICL) and on pro-inflammatory cytokines secretion was evaluated in a cellular model of MKD, chemically obtained treating RAW 264.7 cells with lovastatin and alendronate. The combination of FTIs with the isoprenoid geraniol, was also tested both in this model and in monocytes isolated from MKD patients. Tipifarnib and Lonafarnib proved to revert the ICL lowering and to significantly reduce the lipopolysaccharide-induced cytokines secretion in alendronate-lovastatin-RAW 264.7 cells. This anti-inflammatory effect was amplified combining the use of geraniol with FTIs. The effect of geraniol and Tipifarnib was successfully replicated in MKD patients' monocytes. Tipifarnib and Lonafarnib showed a dramatic anti-inflammatory effect in monocytes where mevalonate pathway was chemically or genetically impaired. LIST OF NON STANDARD ABBREVIATIONS: |
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Authors:
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Annalisa Marcuzzi; Luigina De Leo; Giuliana Decorti; Sergio Crovella; Alberto Tommasini; Alessandra Pontillo |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-3-22 |
Journal Detail:
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Title: Pediatric research Volume: - ISSN: 1530-0447 ISO Abbreviation: - Publication Date: 2011 Mar |
Date Detail:
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Created Date: 2011-3-24 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0100714 Medline TA: Pediatr Res Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Medical Genetic Service [A.M., S.C., A.P.], Laboratory of Immunopathology [A.T.], Institute for Maternal and Child Health "Burlo Garofolo,", Trieste 34134, Italy; Department of Reproductive and Developmental Sciences and Public Health Care [L.D.L.], Department of Life Sciences [G.D.], University of Trieste, Trieste 34137, Italy; Department of Genetics [S.C.], Federal University of Pernambuco, Cidade Universitaria, 50.740-530 Recife, Brazil. |
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