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Updated: Apr 18, 2026
An Orthotopic Bladder Cancer Model for Gene Delivery Studies
Published on: December 1, 2013
Establishment and characterization of a bladder cancer cell line with enhanced doxorubicin resistance by mevalonate
Annemarie Greife1, Jitka Tukova, Christine Steinhoff
1Department of Urology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
Abstract:
Resistance to chemotherapy is a major problem in the treatment of urothelial bladder cancer. Several mechanisms have been identified in resistance to doxorubicin by analysis of resistant urothelial carcinoma (UC) cell lines, prominently activation of drug efflux pumps and diminished apoptosis. We have derived a new doxorubicin-resistant cell line from BFTC-905 UC cells, designated BFTC-905-DOXO-II. A doxorubicin-responsive green fluorescent protein (GFP) reporter assay indicated that resistance in BFTC-905-DOXO-II was not due to increased drug efflux pump activity, whereas caspase-3/7 activation was indeed diminished. Gene expression microarray analysis revealed changes in proapoptotic and antiapoptotic genes, but additionally induction of the mevalonate (cholesterol) biosynthetic pathway. Treatment with simvastatin restored sensitivity of BFTC-905-DOXO-II to doxorubicin to that of the parental cell line. Induction of the mevalonate pathway has been reported as a mechanism of chemoresistance in other cancers; this is the first observation in bladder cancer. Combinations of statins with doxorubicin-containing chemotherapy regimens may provide a therapeutic advantage in such cases.
Insights
Chemoresistance in bladder cancer is linked to diminished apoptosis and cholesterol pathway activation. Simvastatin treatment restored doxorubicin sensitivity in resistant urothelial carcinoma cells, suggesting a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Chemotherapy resistance is a significant challenge in treating urothelial bladder cancer.
- Established mechanisms include increased drug efflux and reduced apoptosis.
Purpose of the Study:
- To investigate novel mechanisms of doxorubicin resistance in urothelial carcinoma (UC).
- To evaluate the therapeutic potential of targeting identified resistance pathways.
Main Methods:
- Development of a doxorubicin-resistant UC cell line (BFTC-905-DOXO-II).
- Assessment of drug efflux activity using a GFP reporter assay.
- Analysis of apoptosis markers (caspase-3/7 activation).
- Gene expression profiling via microarray.
- Treatment with simvastatin to assess pathway modulation and drug sensitivity restoration.
Main Results:
- The resistant cell line BFTC-905-DOXO-II exhibited diminished caspase-3/7 activation, not increased drug efflux.
- Microarray analysis revealed altered expression of apoptosis-related genes and significant induction of the mevalonate (cholesterol) biosynthetic pathway.
- Simvastatin treatment successfully restored doxorubicin sensitivity in the resistant cell line.
Conclusions:
- Diminished apoptosis and mevalonate pathway induction are key mechanisms of doxorubicin resistance in this UC model.
- This is the first report of mevalonate pathway involvement in bladder cancer chemoresistance.
- Combining statins with doxorubicin-based chemotherapy may offer a therapeutic benefit for urothelial bladder cancer patients.
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