Establishment and characterization of a bladder cancer cell line with enhanced doxorubicin resistance by mevalonate pathway activation
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.
KeywordsBladder cancer Chemotherapy Doxorubicin resistance Mevalonate pathway
We are indebted to Drs. M.S. Michel and H.B. Grossman for the generous gifts of bladder cancer cell lines, to J. Heubach, M.Sc., for help with several experiments, and to Dr. Blanka Šediva for the help with statistical analysis. The work was supported by a German Academic Exchange Service (DAAD) visiting professorship (J.H.), the grant No. MSM 0021620819 “Replacement of and support to some vital organs” by the Ministry of Education of the Czech Republic” (J.H.), by a specific student research grant of Charles University SVV- 2014-260 050 (J.T. and J.H.) and by the Christiane und Claudia Hempel Stiftung (W.A.S.).
- 5.Bamias A et al. Prospective, open-label, randomized, phase III study of two dose-dense regimens MVAC versus gemcitabine/cisplatin in patients with inoperable, metastatic or relapsed urothelial cancer: a Hellenic Cooperative Oncology Group study (HE 16/03). Ann Oncol. 2013;24:1011–7.CrossRefPubMedGoogle Scholar
- 9.Serrate C et al. Vinflunin for the treatment of metastatic transitional cell carcinoma: recent evidence from clinical trials and observational studies. Clin Invest 2014;4:305–11.Google Scholar
- 19.Diestra JE et al. Expression of multidrug resistance proteins P-glycoprotein, multidrug resistance protein 1, breast cancer resistance protein and lung resistance related protein in locally advanced bladder cancer treated with neoadjuvant chemotherapy: biological and clinical implications. J Urol. 2003;170:1383–7.CrossRefPubMedGoogle Scholar