Doxorubicin-induced lipid peroxidation and glutathione peroxidase activity in tumor cell lines selected for resistance to doxorubicin.
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.
Benchekroun
M N
MN
Fondation Bergonié, Bordeaux, France.
Pourquier
P
P
Schott
B
B
Robert
J
J
D000818:Animals; D015152:Blotting, Northern; D002460:Cell Line; D004317:Doxorubicin / Q000494:pharmacology*; D004351:Drug Resistance; D015870:Gene Expression; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism*; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism*; D008054:Lipid Peroxides / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D014407:Tumor Cells, Cultured
D008054:Lipid Peroxides; D012333:RNA, Messenger; D004317:Doxorubicin; D005979:Glutathione Peroxidase; D005982:Glutathione Transferase