Journal
TUMOR BIOLOGY
Volume 36, Issue 5, Pages 3293-3300Publisher
SPRINGER
DOI: 10.1007/s13277-014-2959-9
Keywords
Bladder cancer; Chemotherapy; Doxorubicin resistance; Mevalonate pathway
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Funding
- German Academic Exchange Service (DAAD)
- Ministry of Education of the Czech Republic [MSM 0021620819]
- Charles University [SVV- 2014-260 050]
- Christiane und Claudia Hempel Stiftung
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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.
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