title: Establishment and characterization of a bladder cancer cell line with enhanced doxorubicin resistance by mevalonate pathway activation.
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.
authors.affiliation: Department of Urology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Annemarie
authors.initials: A
authors.lastname: Greife
authors.forename: Jitka
authors.initials: J
authors.lastname: Tukova
authors.forename: Christine
authors.initials: C
authors.lastname: Steinhoff
authors.forename: Simon D
authors.initials: SD
authors.lastname: Scott
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Schulz
authors.forename: Jiri
authors.initials: J
authors.lastname: Hatina
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D053898:Biosynthetic Pathways; D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008798:Mevalonic Acid / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology; D059467:Transcriptome; D001749:Urinary Bladder Neoplasms / Q000473:pathology*
chemical_list: D000903:Antibiotics, Antineoplastic; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D004317:Doxorubicin; D019821:Simvastatin; D008798:Mevalonic Acid