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Experimental and Molecular Therapeutics 13: Cell Cycle Components in Therapeutics

Exposure of MCF-7 cells to gemcitabine induces a modification of the large subunit of ribonucleotide reductase, RNR R1

Lars P. Jordheim, Xavier G. Thomas and Charles M. Dumontet
Lars P. Jordheim
INSERM U590, Lyon, France and Service d’Hématologie, Hôpital Edouard Herriot, Lyon, France
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Xavier G. Thomas
INSERM U590, Lyon, France and Service d’Hématologie, Hôpital Edouard Herriot, Lyon, France
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Charles M. Dumontet
INSERM U590, Lyon, France and Service d’Hématologie, Hôpital Edouard Herriot, Lyon, France
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DOI:  Published April 2006
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Proc Amer Assoc Cancer Res, Volume 47, 2006

Abstract

2087

The nucleoside analogue gemcitabine acts partially as a ribonucleotide reductase (RNR) inhibitor. In gemcitabine-resistant MCF-7 cells developed in our laboratory (Jordheim LP et al., Mol Cancer Ther, 2005; 4 (8) : 1268-1276), an increased expression of the large subunit of RNR, R1, seems to play an important role in drug resistance. In order to study the regulation of the expression of RNR R1 by gemcitabine, we exposed parental and gemcitabine-resistant MCF-7 cells to gemcitabine and examined RNR R1 protein by Western blot analysis. The exposure to 1 μM gemcitabine for 24 hours induced an electrophoretic shift in both cell lines. This shift was observed in a time- (0-24 hours) and concentration- (0-100 μM) dependent manner. The shift was specific for gemcitabine as no shift was observed with hydroxyurea nor doxorubicin. In addition, the shift was dependent on intracellular activation of gemcitabine into phosphorylated metabolites, as shown by the absence of electrophoretic shift in deoxycytidine kinase deficient Messa, L1210, A2780 and SW-1573 cells. Incubation of protein extracts from gemcitabine treated cells with protein phosphatase lambda from E. coli did not modify this shift, suggesting that the shift was not due to a phosphorylation of RNR R1. We hypothesize that the shift we observed in gemcitabine exposed cells is a complex of RNR R1 and diphosphorylated gemcitabine which is the intracellular metabolite responsible for RNR inhibition.

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Cancer Research: 66 (8 Supplement)
April 2006
Volume 66, Issue 8 Supplement
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Exposure of MCF-7 cells to gemcitabine induces a modification of the large subunit of ribonucleotide reductase, RNR R1
Lars P. Jordheim, Xavier G. Thomas and Charles M. Dumontet
Cancer Res April 15 2006 (66) (8 Supplement) 492-493;

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Exposure of MCF-7 cells to gemcitabine induces a modification of the large subunit of ribonucleotide reductase, RNR R1
Lars P. Jordheim, Xavier G. Thomas and Charles M. Dumontet
Cancer Res April 15 2006 (66) (8 Supplement) 492-493;
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