期刊
ANTI-CANCER DRUGS
卷 18, 期 4, 页码 389-404出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/CAD.0b013e3280140001
关键词
ATP-binding-cassette transporters; antioxidative enzymes; correlation analysis; cytotoxic drugs; glutathione; resistance
The aim of this work was to determine the functional activities of four different antioxidative enzymes (glutathione reductase, glutathione-S-transferase, glutathione peroxidase, thioredoxin reductase) and the protein expression of three ATP-binding cassette transporters (P-glycoprotein, multidrug resistance protein 1, multidrug resistance protein 2) in a panel of 14 human cancer cell lines. Enzyme activities and transporter expression were then correlated with the in-vitro cytotoxic activities (GI(50) values) of 19 standard antitumor drugs. Analogous data from the National Cancer Institute were used for comparison. The GI(50) values of the platinum complexes, alkylating agents, antimetabolites, topoisomerase inhibitors and antimitotic drugs were determined by crystal violet or 3-(4,5-dimethylthiazol-2yl)2,5-diphenyl tetrazolium bromide assay. Standard enzymatic assays employed to measure the glutathione peroxidase, glutathione-S-transferase, glutathione reductase and thioredoxin reductase activities. The protein expression of the ATP-binding cassette transporter proteins was investigated by the Western-blot method. The 8 method was used to normalize the data before bivariant correlation analysis. Only a few correlations between enzyme and cytotoxic activities of the antitumor agents were found. The GI(50) values for melphalan and camptothecin correlated positively with the activity of glutathione-S-transferase, whereas GI(50) values for methotrexate correlated positively with the cellular activities of both glutathione reductase and thioredoxin reductase. A significant correlation between glutathione reductase and thioredoxin reductase activities was found in our panel of cell lines. Neither P-glycoprotein nor multidrug resistance protein 2 expression could be detected by Western blot analysis in any cell lines investigated, but multidrug resistance protein 1 was consistently observed in all but four lines. Multidrug resistance protein 1 expression correlates positively with the GI(50) values of several drugs, e.g. vinblastine and etoposide, and negatively with the GI(50) values of 5-fluorouracil. The results confirm the complexity of resistance to antitumor agents and show that the GSH-thioredoxin system alone is not a good indication of intrinsic resistance for many of these anticancer drugs.
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