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Non-P-glycoprotein-mediated atypical multidrug resistance in a human bladder cancer cell line
S Naito1, S Hasegawa, A Yokomizo
1Department of Urology, Faculty of Medicine, Kyushu University 71, Fukuoka.
Abstract:
A human bladder cancer cell line resistant to adriamycin (ADM), T24/ADM9 has been established in vitro by exposing T24 parent cells to progressively higher concentrations of the drug over a period of 12 months. The T24/ADM9 cells were found to be 9 times more resistant to ADM than the T24 parent, and showed various degrees of cross-resistance to an ADM derivative, vinea alkaloids and a DNA topoisomerase II (Topo II)-targeting agent, etoposide. No significant differences was observed in the cellular accumulation of ADM between the T24/ADM9 and T24 parent cells. A Northern blot analysis showed an overexpression of multidrug resistance-associated protein (MRP) mRNA, but no overexpression of multidrug resistance-1 (MDR1) mRNA was observed in the T24/ADM9 cells. A flow cytometric analysis showed that the MDR1 gene product, P-glycoprotein (Pgp), is not expressed on the T24/ADM9 cells. T24/ADM9 showed approximately the parental level of DNA Topo II catalytic activity. In Western blot and Northern blot analyses, however, the cellular level of DNA topo II was apparently much lower in T24/ADM9 than in the T24 parent. Thus, these results suggest that a decreased cellular level of DNA Topo II and an overexpression of MRP gene may be responsible for the expression of an MDR phenotype in the T24/ADM9 cells and that such non-Pgp-mediated, atypical MDR may develop in bladder cancer treated with chemotherapy including ADM.
Insights
A new bladder cancer cell line, T24/ADM9, shows resistance to adriamycin (ADM). This atypical multidrug resistance (MDR) is linked to decreased DNA topoisomerase II and increased multidrug resistance-associated protein (MRP), not P-glycoprotein.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Adriamycin (ADM) resistance is a significant challenge in bladder cancer chemotherapy.
- Developing in vitro models is crucial for understanding drug resistance mechanisms.
Purpose of the Study:
- To establish and characterize a novel adriamycin (ADM)-resistant human bladder cancer cell line (T24/ADM9).
- To investigate the molecular mechanisms underlying the observed multidrug resistance (MDR) phenotype.
Main Methods:
- Establishment of T24/ADM9 cell line through prolonged exposure to increasing ADM concentrations.
- Assessment of drug resistance via cell viability assays.
- Analysis of drug accumulation, gene expression (MRP, MDR1), and protein levels (P-glycoprotein, DNA Topoisomerase II) using Northern blot, Western blot, and flow cytometry.
Main Results:
- T24/ADM9 cells exhibited 9-fold resistance to ADM and cross-resistance to etoposide and vinea alkaloids.
- No difference in ADM cellular accumulation was observed.
- Overexpression of multidrug resistance-associated protein (MRP) mRNA was detected, while multidrug resistance-1 (MDR1) mRNA and P-glycoprotein were not expressed.
- A significant decrease in cellular DNA topoisomerase II (Topo II) levels was observed, despite similar catalytic activity.
Conclusions:
- The T24/ADM9 cell line presents a non-P-glycoprotein-mediated MDR phenotype.
- Decreased DNA Topo II levels and MRP overexpression are implicated in this atypical MDR.
- These findings offer insights into chemotherapy resistance mechanisms in bladder cancer and potential therapeutic strategies.
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