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Over-expression of metallothionein and drug-resistance in bladder cancer
1Department of Urology, Okayama University Medical School, Japan.
Abstract:
Metallothionein (MT) in tumor cells has been implicated as one of the factors involved in mechanisms of resistance to anti-cancer drugs, including cis-diaminedichroloplatinum (CDDP) and adriamycin (ADM). The relationship between the expression of MT and chemotherapy with anti-cancer drugs was studied in CDDP- and ADM-resistant human bladder cancer cell lines and tissue samples from clinical cases. In drug-resistant cell lines (T-24/ADM, CI-7/CDDP) established in our laboratory, MT expression was studied by immunohistochemistry using the avidin-biotin peroxidase complex (ABC) method and radioimmunoassay (RIA), using anti-MT antibody. In addition, other potential mechanisms of drug resistance, such as P-glycoprotein expression were examined and the levels of reduced glutathione (GSH), oxidized glutathione (GSSG) and glutathione-S-transferase (GST) determined in these cell lines. The results of these investigations demonstrate that the expression of MT in resistant cell lines increased 2.1- and 2.5-fold when compared with parent cell lines (CI-7, T-24). GSH, GSSG and GST levels were unchanged and P-glycoprotein was not over-expressed. A total of 120 tissue samples from 35 clinical cases of bladder cancer, before and after chemotherapy, were stained for MT which was detected in 10 of the 35 cases before chemotherapy. The incidence of MT expression was significantly higher (p < 0.05) in cases with lower pathological tumor grades.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Metallothionein (MT) expression increased in drug-resistant bladder cancer cells, suggesting its role in chemotherapy resistance. MT was also detected in clinical bladder cancer tissues, particularly in lower-grade tumors.
Area of Science:
- Oncology
- Biochemistry
Background:
- Metallothionein (MT) is implicated in anticancer drug resistance.
- Understanding MT's role is crucial for overcoming resistance to drugs like cisplatin (CDDP) and adriamycin (ADM).
Purpose of the Study:
- To investigate the relationship between MT expression and resistance to CDDP and ADM in human bladder cancer.
- To examine MT expression in both resistant cell lines and clinical bladder cancer tissue samples.
Main Methods:
- Immunohistochemistry (ABC method) and radioimmunoassay (RIA) were used to assess MT expression in resistant cell lines (T-24/ADM, CI-7/CDDP).
- Other resistance mechanisms, including P-glycoprotein, reduced glutathione (GSH), oxidized glutathione (GSSG), and glutathione-S-transferase (GST), were also analyzed.
- MT expression was evaluated in 120 clinical bladder cancer tissue samples.
Main Results:
- MT expression was significantly elevated (2.1- and 2.5-fold) in resistant cell lines compared to parent lines.
- Levels of GSH, GSSG, and GST remained unchanged, and P-glycoprotein was not over-expressed in resistant cells.
- MT was detected in 10 of 35 clinical bladder cancer cases before chemotherapy, with higher incidence in lower pathological tumor grades (p < 0.05).
Conclusions:
- Increased MT expression is associated with resistance to CDDP and ADM in bladder cancer cells.
- MT may play a role in bladder cancer chemoresistance, independent of P-glycoprotein and glutathione pathways.
- MT detection in clinical samples suggests potential prognostic or predictive value, especially in lower-grade tumors.