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Doxorubicin-induced lipid peroxidation and glutathione peroxidase activity in tumor cell lines selected for resistance to doxorubicin

Abstract : Doxorubicin-induced lipid peroxidation was evaluated in four human or murine cell strains in culture and in their doxorubicin-resistant variants, by the quantification of malondialdehyde produced after a 2-h incubation of cells with the drug. Significantly increased malondialdehyde levels were obtained 24 h after doxorubicin treatment in three of the wild-type cell lines with doses as low as 0.05-0.1 micrograms/ml, which is within an order of magnitude of the concentration of the drug which inhibits cell growth by 50%. This production of malondialdehyde was abolished in two doxorubicin-resistant strains, even with high doses of drug (100-300 micrograms/ml), but was maintained in the third resistant line. No malondialdehyde production was observed in the fourth cell line, sensitive or resistant. It is remarkable that an enhancement of selenium-dependent and non-selenium-dependent glutathione peroxidase activities was exhibited during the acquisition of resistance to doxorubicin in the two first lines, but not in the third, whereas a constitutively high non-selenium-dependent glutathione peroxidase activity existed in the doxorubicin-sensitive and doxorubicin-resistant variants of the fourth cell line. Gene expression of selenium-dependent glutathione peroxidase and of glutathione S-transferase pi, which is known partially to bear a non-selenium-dependent glutathione peroxidase activity, were correlated with the corresponding enzyme activities. It appears, therefore, that the already known enhancement of glutathione peroxidase activity and expression in doxorubicin-resistant cell lines has a quantifiable consequence upon doxorubicin-induced lipid peroxidation and may have consequences in the mechanism of resistance to this drug.
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Contributor : Philippe Pourquier Connect in order to contact the contributor
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M. Nabil Benchekroun, Philippe Pourquier, Brigitte Schott, Jacques Robert. Doxorubicin-induced lipid peroxidation and glutathione peroxidase activity in tumor cell lines selected for resistance to doxorubicin. European Journal of Biochemistry, Wiley, 1993, 211 (1-2), pp.141-146. ⟨10.1111/j.1432-1033.1993.tb19880.x⟩. ⟨inserm-02438185⟩



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