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Berlin Brandenburg

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  • 1
    Language: English
    In: The Journal of Urology, April 2012, Vol.187(4), pp.e432-e432
    Keywords: Medicine
    ISSN: 0022-5347
    E-ISSN: 1527-3792
    Source: ScienceDirect Journals (Elsevier)
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  • 2
    Language: English
    In: BMC cancer, 07 April 2015, Vol.15, pp.224
    Description: Acquired resistance to standard chemotherapy causes treatment failure in patients with metastatic bladder cancer. Overexpression of pro-survival Bcl-2 family proteins has been associated with a poor chemotherapeutic response, suggesting that Bcl-2-targeted therapy may be a feasible strategy in patients with these tumors. The small-molecule pan-Bcl-2 inhibitor (-)-gossypol (AT-101) is known to induce apoptotic cell death, but can also induce autophagy through release of the pro-autophagic BH3 only protein Beclin-1 from Bcl-2. The potential therapeutic effects of (-)-gossypol in chemoresistant bladder cancer and the role of autophagy in this context are hitherto unknown. Cisplatin (5637(r)CDDP(1000), RT4(r)CDDP(1000)) and gemcitabine (5637(r)GEMCI(20), RT4(r)GEMCI(20)) chemoresistant sub-lines of the chemo-sensitive bladder cancer cell lines 5637 and RT4 were established for the investigation of acquired resistance mechanisms. Cell lines carrying a stable lentiviral knockdown of the core autophagy regulator ATG5 were created from chemosensitive 5637 and chemoresistant 5637(r)GEMCI(20) and 5637(r)CDDP(1000) cell lines. Cell death and autophagy were quantified by FACS analysis of propidium iodide, Annexin and Lysotracker staining, as well as LC3 translocation. Here we demonstrate that (-)-gossypol induces an apoptotic type of cell death in 5637 and RT4 cells which is partially inhibited by the pan-caspase inhibitor z-VAD. Cisplatin- and gemcitabine-resistant bladder cancer cells exhibit enhanced basal and drug-induced autophagosome formation and lysosomal activity which is accompanied by an attenuated apoptotic cell death after treatment with both (-)-gossypol and ABT-737, a Bcl-2 inhibitor which spares Mcl-1, in comparison to parental cells. Knockdown of ATG5 and inhibition of autophagy by 3-MA had no discernible effect on apoptotic cell death induced by (-)-gossypol and ABT-737 in parental 5637 cells, but evoked a significant increase in early apoptosis and overall cell death in BH3 mimetic-treated 5637(r)GEMCI(20) and 5637(r)CDDP(1000) cells. Our findings show for the first time that (-)-gossypol concomitantly triggers apoptosis and a cytoprotective type of autophagy in bladder cancer and support the notion that enhanced autophagy may underlie the chemoresistant phenotype of these tumors. Simultaneous targeting of Bcl-2 proteins and the autophagy pathway may be an efficient new strategy to overcome their "autophagy addiction" and acquired resistance to current therapy.
    Keywords: Gossypol -- Analogs & Derivatives ; Proto-Oncogene Proteins C-Bcl-2 -- Genetics ; Urinary Bladder Neoplasms -- Drug Therapy
    E-ISSN: 1471-2407
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  • 3
    In: Vallo, Stefan and Rutz, Jochen and Kautsch, Miriam and Winkelmann, Ria and Michaelis, Martin and Wezel, Felix and Bartsch, Georg and Haferkamp, Axel and Rothweiler, Florian and Blaheta, Roman A and Cinatl, Jindrich (2017) Blocking integrin β1 decreases adhesion in chemoresistant urothelial cancer cell lines. Oncology letters, 14 (5). pp. 5513-5518.
    Description: Treatment failure in metastatic bladder cancer is commonly caused by acquisition of resistance to chemotherapy in association with tumor progression. Since alterations of integrins can influence the adhesive and invasive behaviors of urothelial bladder cancer cell lines, the present study aimed to evaluate the role of integrins in bladder cancer cells with acquired resistance to standard first-line chemotherapy with gemcitabine, and cisplatin. Therefore, four gemcitabine- and four cisplatin-resistant sublines out of a panel of four parental urothelial bladder cancer cell lines (TCC-SUP, HT1376, T24, and 5637) were used. Expression of integrin subunits α3, α5, α6, β1, β3, and β4 was detected using flow cytometry. Adhesion and chemotaxis were analyzed. For functional assays, integrin β1 was attenuated with a blocking antibody. In untreated cells, chemotaxis was upregulated in 3/4 gemcitabine-resistant sublines. In cisplatin-resistant cells, chemotaxis was enhanced in 2/4 cell lines. Acquired chemoresistance induced the upregulation of integrin β1 in all four tested gemcitabine-resistant sublines, as well as an upregulation in 3/4 cisplatin-resistant sublines compared with parental cell lines. Following the inhibition of integrin β1, adhesion to extracellular matrix components was downregulated in 3/4 gemcitabine-resistant sublines and in all four tested cisplatin-resistant sublines. Since integrin β1 is frequently upregulated in chemoresistant urothelial cancer cell lines and inhibition of integrin β1 may influence adhesion, further studies are warranted to evaluate integrin β1 as a potential therapeutic target for bladder cancer.
    Keywords: RM Therapeutics. Pharmacology
    ISSN: 1792-1074
    Source: University of Kent
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  • 4
    Language: English
    In: Translational Oncology, June 2015, Vol.8(3), pp.210-216
    Description: 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 GEMCI ), 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 model can reproduce clinically relevant results and may be suitable to identify novel substances for the treatment of metastatic bladder cancer.
    Keywords: Medicine
    ISSN: 1936-5233
    E-ISSN: 1936-5233
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  • 5
    In: Vallo, Stefan and K�pp, Raoul and Michaelis, Martin and Rothweiler, Florian and Bartsch, Georg and Brandt, Maximilian and Gust, Kilian and Wezel, Felix and Blaheta, Roman and Haferkamp, Axel and Cinatl, Jindrich (2017) Resistance to nanoparticle albumin-bound paclitaxel is mediated by ABCB1 in urothelial cancer cells. Oncology Letters, 13 (6).
    Description: Nanoparticle albumin‑bound (nab)-paclitaxel appears to exhibit better response rates in patients with metastatic urothelial cancer of the bladder whom are pretreated with nab-paclitaxel compared with conventional paclitaxel. Paclitaxel may induce multidrug resistance in patients with cancer, while the mechanisms of resistance against paclitaxel are manifold. These include reduced function of pro‑apoptotic proteins, mutations of tubulin and overexpression of the drug transporter adenosine 5'‑triphosphate‑binding cassette transporter subfamily B, member 1 (ABCB1). To evaluate the role of ABCB1 in nab‑paclitaxel resistance in urothelial cancer cells, the bladder cancer cell lines T24 and TCC‑SUP, as well as sub‑lines with acquired resistance against gemcitabine (T24rGEMCI20 and TCC‑SUPrGEMCI20) and vinblastine (T24rVBL20 and TCC‑SUPrVBL20) were examined. For the functional inhibition of ABCB1, multi-tyrosine kinase inhibitors with ABCB1‑inhibiting properties, including cabozantinib and crizotinib, were used. Additional functional assessment was performed with cell lines stably transduced with a lentiviral vector encoding for ABCB1, and protein expression was determined by western blotting. It was indicated that cell lines overexpressing ABCB1 exhibited similar resistance profiles to nab‑paclitaxel and paclitaxel. Cabozantinib and crizotinib sensitized tumor cells to nab‑paclitaxel and paclitaxel in the same dose‑dependent manner in cell lines overexpressing ABCB1, without altering the downstream signaling of tyrosine kinases. These results suggest that the overexpression of ABCB1 confers resistance to nab‑paclitaxel in urothelial cancer cells. Additionally, small molecules may overcome resistance to anticancer drugs that are substrates of ABCB1.
    ISSN: 1792-1074
    Source: University of Kent
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  • 6
    Language: English
    In: Oncology Letters, 11/2017, Vol.14(5), pp.5513-5518
    Description: Treatment failure in metastatic bladder cancer is commonly caused by acquisition of resistance to chemotherapy in association with tumor progression. Since alterations of integrins can influence the adhesive and invasive behaviors of urothelial bladder cancer cell lines, the present study aimed to evaluate the role of integrins in bladder cancer cells with acquired resistance to standard first-line chemotherapy with gemcitabine, and cisplatin. Therefore, four gemcitabine- and four cisplatin-resistant sublines out of a panel of four parental urothelial bladder cancer cell lines (TCC-SUP, HT1376, T24, and 5637) were used. Expression of integrin subunits α3, α5, α6, β1, β3, and β4 was detected using flow cytometry. Adhesion and chemotaxis were analyzed. For functional assays, integrin β1 was attenuated with a blocking antibody. In untreated cells, chemotaxis was upregulated in 3/4 gemcitabine-resistant sublines. In cisplatin-resistant cells, chemotaxis was enhanced in 2/4 cell lines. Acquired chemoresistance induced the upregulation of integrin β1 in all four tested gemcitabine-resistant sublines, as well as an upregulation in 3/4 cisplatin-resistant sublines compared with parental cell lines. Following the inhibition of integrin β1, adhesion to extracellular matrix components was downregulated in 3/4 gemcitabine-resistant sublines and in all four tested cisplatin-resistant sublines. Since integrin β1 is frequently upregulated in chemoresistant urothelial cancer cell lines and inhibition of integrin β1 may influence adhesion, further studies are warranted to evaluate integrin β1 as a potential therapeutic target for bladder cancer in vivo .
    Keywords: Adhesion ; Acquired Resistance ; Cancer Cell Line Collection ; Chemotaxis ; Cisplatin ; Gemcitabine ; Integrin Β1 ; Urothelial Cancer
    ISSN: 1792-1074
    E-ISSN: 1792-1082
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  • 7
    Language: English
    In: Oncology Letters, 06/2017, Vol.13(6), pp.4085-4092
    Description: Nanoparticle albumin-bound (nab)-paclitaxel appears to exhibit better response rates in patients with metastatic urothelial cancer of the bladder whom are pretreated with nab-paclitaxel compared with conventional paclitaxel. Paclitaxel may induce multidrug resistance in patients with cancer, while the mechanisms of resistance against paclitaxel are manifold. These include reduced function of pro-apoptotic proteins, mutations of tubulin and overexpression of the drug transporter adenosine 5′-triphosphate-binding cassette transporter subfamily B, member 1 (ABCB1). To evaluate the role of ABCB1 in nab-paclitaxel resistance in urothelial cancer cells, the bladder cancer cell lines T24 and TCC-SUP, as well as sub-lines with acquired resistance against gemcitabine (T24 r GEMCI 20 and TCC-SUP r GEMCI 20 ) and vinblastine (T24 r VBL 20 and TCC-SUP r VBL 20 ) were examined. For the functional inhibition of ABCB1, multi-tyrosine kinase inhibitors with ABCB1-inhibiting properties, including cabozantinib and crizotinib, were used. Additional functional assessment was performed with cell lines stably transduced with a lentiviral vector encoding for ABCB1, and protein expression was determined by western blotting. It was indicated that cell lines overexpressing ABCB1 exhibited similar resistance profiles to nab-paclitaxel and paclitaxel. Cabozantinib and crizotinib sensitized tumor cells to nab-paclitaxel and paclitaxel in the same dose-dependent manner in cell lines overexpressing ABCB1, without altering the downstream signaling of tyrosine kinases. These results suggest that the overexpression of ABCB1 confers resistance to nab-paclitaxel in urothelial cancer cells. Additionally, small molecules may overcome resistance to anticancer drugs that are substrates of ABCB1.
    Keywords: Abcb1 ; Acquired Resistance ; Bladder Cancer ; Cabozantinib ; Cancer Cell Line Collection ; Crizotinib ; Nanoparticle Albumin-Bound Paclitaxel
    ISSN: 1792-1074
    E-ISSN: 1792-1082
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  • 8
    In: Vallo, Stefan and Michaelis, Martin and Gust, Kilian M and Black, Peter C and Rothweiler, Florian and Kvasnicka, Hans-Michael and Blaheta, Roman A and Brandt, Maximilian P and Wezel, Felix and Haferkamp, Axel and Cinatl, Jindrich (2016) Dasatinib enhances tumor growth in gemcitabine-resistant orthotopic bladder cancer xenografts. BMC research notes, 9 (1). p. 454.
    Description: BACKGROUND Systemic chemotherapy with gemcitabine and cisplatin is standard of care for patients with metastatic urothelial bladder cancer. However, resistance formation is common after initial response. The protein Src is known as a proto-oncogene, which is overexpressed in various human cancers. Since there are controversial reports about the role of Src in bladder cancer, we evaluated the efficacy of the Src kinase inhibitor dasatinib in the urothelial bladder cancer cell line RT112 and its gemcitabine-resistant sub-line RT112(r)GEMCI(20) in vitro and in vivo. METHODS RT112 urothelial cancer cells were adapted to growth in the presence of 20 ng/ml gemcitabine (RT112(r)GEMCI(20)) by continuous cultivation at increasing drug concentrations. Cell viability was determined by MTT assay, cell growth kinetics were determined by cell count, protein levels were measured by western blot, and cell migration was evaluated by scratch assays. In vivo tumor growth was tested in a murine orthotopic xenograft model using bioluminescent imaging. RESULTS Dasatinib exerted similar effects on Src signaling in RT112 and RT112(r)GEMCI(20) cells but RT112(r)GEMCI(20) cells were less sensitive to dasatinib-induced anti-cancer effects (half maximal inhibitory concentration (IC50) of dasatinib in RT112 cells: 349.2 ± 67.2 nM; IC50 of dasatinib in RT112(r)GEMCI(20) cells: 1081.1 ± 239.2 nM). Dasatinib inhibited migration of chemo-naive and gemcitabine-resistant cells. Most strikingly, dasatinib treatment reduced RT112 tumor growth and muscle invasion in orthotopic xenografts, while it was associated with increased size and muscle-invasive growth in RT112(r)GEMCI(20) tumors. CONCLUSION Dasatinib should be considered with care for the treatment of urothelial cancer, in particular for therapy-refractory cases.
    Keywords: RM Therapeutics. Pharmacology
    ISSN: 1756-0500
    Source: University of Kent
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  • 9
    Language: English
    In: BMC research notes, 27 September 2016, Vol.9(1), pp.454
    Description: Systemic chemotherapy with gemcitabine and cisplatin is standard of care for patients with metastatic urothelial bladder cancer. However, resistance formation is common after initial response. The protein Src is known as a proto-oncogene, which is overexpressed in various human cancers. Since there are controversial reports about the role of Src in bladder cancer, we evaluated the efficacy of the Src kinase inhibitor dasatinib in the urothelial bladder cancer cell line RT112 and its gemcitabine-resistant sub-line RT112GEMCI in vitro and in vivo. RT112 urothelial cancer cells were adapted to growth in the presence of 20 ng/ml gemcitabine (RT112GEMCI) by continuous cultivation at increasing drug concentrations. Cell viability was determined by MTT assay, cell growth kinetics were determined by cell count, protein levels were measured by western blot, and cell migration was evaluated by scratch assays. In vivo tumor growth was tested in a murine orthotopic xenograft model using bioluminescent imaging. Dasatinib exerted similar effects on Src signaling in RT112 and RT112GEMCI cells but RT112GEMCI cells were less sensitive to dasatinib-induced anti-cancer effects (half maximal inhibitory concentration (IC) of dasatinib in RT112 cells: 349.2 ± 67.2 nM; IC of dasatinib in RT112GEMCI cells: 1081.1 ± 239.2 nM). Dasatinib inhibited migration of chemo-naive and gemcitabine-resistant cells. Most strikingly, dasatinib treatment reduced RT112 tumor growth and muscle invasion in orthotopic xenografts, while it was associated with increased size and muscle-invasive growth in RT112GEMCI tumors. Dasatinib should be considered with care for the treatment of urothelial cancer, in particular for therapy-refractory cases.
    Keywords: Acquired Resistance ; Cancer Cell Line Collection ; Dasatinib ; Gemcitabine ; Orthotopic Xenograft Model ; Urothelial Bladder Cancer
    E-ISSN: 1756-0500
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  • 10
    Language: English
    Description: Background: Systemic chemotherapy with gemcitabine and cisplatin is standard of care for patients with metastatic urothelial bladder cancer. However, resistance formation is common after initial response. The protein Src is known as a proto-oncogene, which is overexpressed in various human cancers. Since there are controversial reports about the role of Src in bladder cancer, we evaluated the efficacy of the Src kinase inhibitor dasatinib in the urothelial bladder cancer cell line RT112 and its gemcitabine-resistant sub-line RT112rGEMCI20 in vitro and in vivo. Methods: RT112 urothelial cancer cells were adapted to growth in the presence of 20 ng/ml gemcitabine (RT112rGEMCI20) by continuous cultivation at increasing drug concentrations. Cell viability was determined by MTT assay, cell growth kinetics were determined...
    Source: DataCite
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