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Abstract
BackgroundSystemic 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.MethodsRT112 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 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.ResultsDasatinib exerted similar effects on Src signaling in RT112 and RT112rGEMCI20 cells but RT112rGEMCI20 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 RT112rGEMCI20 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 RT112rGEMCI20 tumors.ConclusionDasatinib should be considered with care for the treatment of urothelial cancer, in particular for therapy-refractory cases.
Highlights
Systemic chemotherapy with gemcitabine and cisplatin is standard of care for patients with metastatic urothelial bladder cancer
In vitro effects of dasatinib on RT112 and RT112rGEMCI20 cells RT112rGEMCI20 cells (IC50: 1081.1 ± 239.2 nM) showed a 3.1-fold decreased sensitivity to dasatinib compared to parental RT112 cells (IC50: 349.2 ± 67.2 nM)
In this study, we compared the effects of the Src inhibitor dasatinib on the urothelial cancer cell line RT112 and its gemcitabine-resistant sub-line RT112rGEMCI20 in cell culture and in an orthotopic bladder cancer xenograft model in mice
Summary
Systemic chemotherapy with gemcitabine and cisplatin is standard of care for patients with metastatic urothelial bladder cancer. 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. First-line therapy regimens for metastatic disease include gemcitabine and cisplatin (GC) as standard of care resulting in response rates of 40–70 %. The c-Src proto-oncogene has been strongly implicated in the development, growth, progression, and metastasis of a number of human cancers including those of colon, breast, pancreas, and brain [5, 6]. Src inhibition caused anti-cancer effects in some bladder cancer cell lines (including RT112) and animal models [9, Vallo et al BMC Res Notes (2016) 9:454
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