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  • Blaheta, Roman A  (2)
  • Kent Academic Repository (University of Kent)  (2)
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  • Kent Academic Repository (University of Kent)  (2)
  • 1
    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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  • 2
    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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