Effect of Glutathione and its Related Enzymes on Chemosensitivity of Renal Cell Carcinoma and Bladder Carcinoma Cell Lines

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Abstract
Glutathione and glutathione-related enzymes have been implicated in sensitivity of tumors to chemotherapeutic drugs. In the present study, glutathione and the activity of its related enzymes were quantitated in 4 renal cell carcinoma cell lines and 4 bladder carcinoma cell lines. The expression of glutathione-s-transferase pi and alpha in each cell line was analyzed by immunoblot analysis. The relationships between glutathione levels, glutathione peroxidase activity and glutathione-s-transferase activity and tumor sensitivity to cisplatinum, doxorubicin and vinblastine were determined by linear regression analysis. Glutathione levels were positively related to cisplatinum resistance in both renal cell carcinoma and bladder carcinoma cell lines and to doxorubicin resistance in bladder carcinoma cell lines. A positive correlation between glutathione peroxidase activity and doxorubicin resistance was identified in renal cell carcinoma cell lines, but no correlation was noted in bladder carcinoma cell lines. No significant correlation was apparent between glutathione-s-transferase activity and sensitivity to any of the drugs tested in this study. To further clarify the relationship between glutathione levels and the cytotoxicity of the drugs, we evaluated the effect of glutathione depletion by L-buthionine sulfoximine on the cytotoxicity of the drugs in bladder carcinoma cell lines. Glutathione depletion enhanced cisplatinum cytotoxicity 1.3- to 1.7-fold and doxorubicin cytotoxicity by 1.45- to 11.2-fold. Glutathione depletion did not change vinblastine cytotoxicity. The present study demonstrates that glutathione and its related enzymes affect sensitivity to cisplatinum or doxorubicin. The drug resistance mechanism elicited by glutathione and its related enzymes in these tumors needs further elucidation so that chemotherapeutic regimens may be modified.