Distribution intracellulaire des anthracyclines : implication dans le processus de mort cellulaire induite et le phénotype de résistance pléiotrope

Abstract : The main cause of failure in anthracyclines chemotherapy is the classical phenotype of multidrug resistance (MDR). The first part of this study characterized cytoplasmic sequestration of daunorubicin (DNR) mediated by P-glycoprotein (P-gp) and its role in DNR cytotoxicity. In vitro experiments with sensitive and resistant cell lines using image analysis, demonstrated that Golgi apparatus is the main target of DNR sequestration. The fluorescence spectra of DNR in both celllines inside Golgi suggested specific interactions between DNR and lipids in resistant cell line. P-gp inhibtion by combinations of suboptimal concentrations of modulators including PSC-833 known to be acting on intracellular lipids reverted DNR cytotoxicity without modulating its intracellular accumulation but allowed DNR redistribution inside cytoplasm. DNR accumulation was modulated by PSC-833. Additionnaly DNR cytoplasmic sequestration was partially moduled by PSC-833. The second part of this work measured in vitro the impact of idarubicin (IDA) lipophilicity as compared with epirubicin (EPI), on cellular incorporation and cell response. These parameters were evaluated in relation with P-gp or multidrug resistance related protein (MRP) overexpression. IDA incorporation is faster, but as EPI, IDA is a substrate for P-gp. IDA is distinguished by delayed effiux in presence of MRP. Moreover IDA was characterized by a larger pattern of subcellular distribution. These later properties implied a higher cytotoxicity for IDA whatever the cell lines. G2/M arrest of cells and/or effective P53 induction by both anthracyclines traduced DNA damages but were not sufficient to specifically activate apoptosis. The early production of ceramides was higher after IDA treatment, and seemed to be specifically associated with apoptosis. The data collected during this study suggested that in addition its nuclear target, IDA induced cell death by acting onto cytoplasmic targets.
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Corinne Bour Dill. Distribution intracellulaire des anthracyclines : implication dans le processus de mort cellulaire induite et le phénotype de résistance pléiotrope. Médecine humaine et pathologie. Université Henri Poincaré - Nancy 1, 2001. Français. ⟨NNT : 2001NAN11301⟩. ⟨tel-01754383⟩

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