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Thesis

French

ID: <

10670/1.n3qhwm

>

Where these data come from
Repression cobalamin-dependent signaling pathways of MDR-1 gene : A new pharmacological target for chemotherapy?

Abstract

A key factor of chemioresistance is an increased expression of MDR-1 gene, partly controlled by cellular methylation reactions. Until now, the physiology of these reactions is not clearly known. The main intracellular metabolic pathway, generating methyl donors, is the methionine cycle, the activity of which is strongly depending on B-group vitamins (B12, B9). Thus, MDR-1 gene expression may be controlled by the activity of the methionine cycle and consequently presence of these vitamins. The aim of this study is to determine if, and to elucidate how, the methionine cycle influences the MDR-1 gene expression. Chromatography, pharmacotoxicology, cell culture techniques, gene and protein expression studies have been used on the human hepatocarcinoma cell line HepG2. We showed that cobalamin-induced MDR-1 gene repression was associated with phospholipase D activation, Akt phosphorylation, and Cox-2 co-repression in a complex and intricated manner. We may suggest that targeting these pathways could potentiate chimotherapy. This work shoiuld allow 1) a better understanding of mechanisms explaining why some anticancer agents may become inactive, 2) to optimize utilisation of these agents in relationship with MDR-1 gene expression and the B vitamin status, 3) to evaluate impacts of nutritionnal factors (cobalamine) in MDR-1 gene expression and 4) probably developp possible ways to improve chemotherapy

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