RESUMO
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Assuntos
Humanos , Masculino , Pré-Escolar , Adolescente , Colina Quinase/deficiência , Citidina Difosfato Colina/uso terapêutico , Colina Quinase/genética , Erros Inatos do Metabolismo Lipídico/tratamento farmacológico , Erros Inatos do Metabolismo Lipídico/enzimologia , Erros Inatos do Metabolismo Lipídico/genética , Fosfatidilcolinas/metabolismoRESUMO
Background. Choline kinase alpha (ChoKα) is a critical enzyme in the synthesis of phosphatidylcholine, a major structural component of eukaryotic cell membranes. ChoKα is overexpressed in a large variety of tumor cells and has been proposed as a target for personalized medicine, both in cancer therapy and rheumatoid arthritis. Materials and methods. Triterpene quinone methides (TPQ) bioactive compounds isolated from plants of the Celastraceae family and a set of their semisynthetic derivatives were tested against the recombinant human ChoKα. Those found active as potent enzymatic inhibitors were tested in vitro for antiproliferative activity against HT29 colorectal adenocarcinoma cells, and one of the active compounds was tested for in vivo antitumoral activity in mice xenographs of HT29 cells. Results. Among 59 natural and semisynthetic TPQs tested in an ex vivo system, 14 were highly active as inhibitors of the enzyme ChoKα with IC50 <10 μM. Nine of these were potent antiproliferative agents (IC50 <10 μM) against tumor cells. At least one compound was identified as a new antitumoral drug based on its in vivo activity against xenographs of human HT-29 colon adenocarcinoma cells. Conclusions. The identification of a new family of natural and semisynthetic compounds with potent inhibitory activity against ChoKα and both in vitro antiproliferative and in vivo antitumoral activity supports further research on these inhibitors as potential anticancer agents. Their likely role as antiproliferative drugs deserves further studies in models of rheumatoid arthritis (AU)
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Assuntos
Colina Quinase/análise , Colina Quinase/metabolismo , Produtos Biológicos/metabolismo , Produtos Biológicos/farmacocinética , Produtos Biológicos/uso terapêutico , Produtos Biológicos/análise , Produtos Biológicos/imunologia , Fosfatidilcolina-Esterol O-Aciltransferase , Fosfatidilcolina-Esterol O-Aciltransferase/metabolismoRESUMO
AIM: The relevance of the cytidine diphosphate-choline and Rho GTPases pathways in the pathogenesis of cancer has been previously demonstrated. We investigate by a case-control association study if genetics variants in these pathways are associated with risk of developing lung cancer. METHODS: Thirty-seven tag SNPs were evaluated as risk factor of NSCLC in 897 cases and 904 controls. RESULTS: Six SNPs were nominally associated with lung cancer risk, which were not significant after the Bonferroni correction for multiple comparisons. No association was observed with the remaining 31 analyzed SNPs, neither it was found significant in haplotype frequencies. CONCLUSIONS: Although the implication of the two pathways investigated in our study in carcinogenesis is well established, our null results suggest that common genetic variants in CDP-choline and Rho GTPases-related genes are not risk factors for lung cancer (AU)
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