title: Drug-Resistant Urothelial Cancer Cell Lines Display Diverse Sensitivity Profiles to Potential Second-Line Therapeutics.
abstract: Combination chemotherapy with gemcitabine and cisplatin in patients with metastatic urothelial cancer of the bladder frequently results in the development of acquired drug resistance. Availability of cell culture models with acquired resistance could help to identify candidate treatments for an efficient second-line therapy. Six cisplatin- and six gemcitabine-resistant cell lines were established. Cell viability assays were performed to evaluate the sensitivity to 16 different chemotherapeutic substances. The activity of the drug transporter ATP-binding cassette transporter, subfamily B, member 1 (ABCB1, a critical mediator of multidrug resistance in cancer) was evaluated using fluorescent ABCB1 substrates. For functional assessment, cells overexpressing ABCB1 were generated by transduction with a lentiviral vector encoding for ABCB1, while zosuquidar was used for selective inhibition. In this study, 8 of 12 gemcitabine- or cisplatin-resistant cell lines were cross-resistant to carboplatin, 5 to pemetrexed, 4 to methotrexate, 3 to oxaliplatin, 5-fluorouracil, and paclitaxel, and 2 to cabazitaxel, larotaxel, docetaxel, topotecan, doxorubicin, and mitomycin c, and 1 of 12 cell lines was cross-resistant to vinflunine and vinblastine. In one cell line with acquired resistance to gemcitabine (TCC-SUP(r)GEMCI(20)), cross-resistance seemed to be mediated by ABCB1 expression. Our model identified the vinca alkaloids vinblastine and vinflunine, in Europe an already approved second-line therapeutic for metastatic bladder cancer, as the most effective compounds in urothelial cancer cells with acquired resistance to gemcitabine or cisplatin. These results demonstrate that this in vitro model can reproduce clinically relevant results and may be suitable to identify novel substances for the treatment of metastatic bladder cancer.
authors.affiliation: Institute of Medical Virology, University Hospital Frankfurt, Frankfurt am Main, Germany; Department of Urology, University Hospital Frankfurt, Frankfurt am Main, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Vallo
authors.affiliation: Centre for Molecular Processing and School of Biosciences, University of Kent, Canterbury, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: Michaelis
authors.affiliation: Institute of Medical Virology, University Hospital Frankfurt, Frankfurt am Main, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Rothweiler
authors.affiliation: Department of Urology, University Hospital Frankfurt, Frankfurt am Main, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Bartsch
authors.affiliation: Department of Urology, University Hospital Frankfurt, Frankfurt am Main, Germany.
authors.forename: Kilian M
authors.initials: KM
authors.lastname: Gust
authors.affiliation: Institute of Medical Virology, University Hospital Frankfurt, Frankfurt am Main, Germany.
authors.forename: Dominik M
authors.initials: DM
authors.lastname: Limbart
authors.affiliation: Department of Radiation Therapy and Oncology, University Hospital Frankfurt, Frankfurt am Main, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: Rödel
authors.affiliation: Department of Urology, University Hospital Mannheim, Mannheim, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Wezel
authors.affiliation: Department of Urology, University Hospital Frankfurt, Frankfurt am Main, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Haferkamp
authors.affiliation: Institute of Medical Virology, University Hospital Frankfurt, Frankfurt am Main, Germany. Electronic address: cinatl@em.uni-frankfurt.de.
authors.forename: Jindrich
authors.initials: J
authors.lastname: Cinatl