The Journal of urology · 2007
Bacillus Calmette-Guerin inhibits apoptosis in human urothelial carcinoma cell lines in response to cytotoxic injury.
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Chen Fanghong, Zhang Guanjian, Cao Yanli, Payne Ryan, See William A
Аннотация
PURPOSE: By inducing cell cycle arrest at the G1/S transition bacillus Calmette-Guerin has been shown to have a direct antiproliferative effect on urothelial carcinoma cell lines. In other systems cell cycle arrest has been shown to confer a relative state of apoptotic resistance. We assessed the effect of bacillus Calmette-Guerin on the susceptibility of urothelial carcinoma cells to apoptotic stimuli.
MATERIALS AND METHODS: The human UC cell lines T24 and 253J (American Type Cell Culture, Rockville, Maryland) were used to evaluate the effect of bacillus Calmette-Guerin or antibody mediated alpha5beta1cross-linking on apoptosis and apoptotic sensitivity. Following treatment baseline apoptosis and the response to the apoptotic inducing agent camptothecin was evaluated using assays for caspase 3 activation and DNA fragmentation. Pharmacological blockade of signaling pathways known to be activated in response to bacillus Calmette-Guerin/alpha5beta1 cross-linking was used to assess the role of these pathways in the bacillus Calmette-Guerin apoptotic response. A final series of experiments used the MTT assay to study the impact of bacillus Calmette-Guerin pretreatment on the cytotoxicity of the antineoplastic agent mitomycin C.
RESULTS: Treatment with bacillus Calmette-Guerin failed to induce apoptosis, as measured by caspase 3 activation or DNA laddering. Bacillus Calmette-Guerin pretreatment significantly inhibited the induction of apoptosis in response to camptothecin. These effects were reproduced by antibody mediated cross-linking of alpha5beta1 integrin. Pharmacological inhibition of nuclear factor kappaB and/or AP1 signaling pathways reversed the anti-apoptotic effect of bacillus Calmette-Guerin. Mitomycin C cytotoxicity was significantly decreased by bacillus Calmette-Guerin pretreatment.
CONCLUSIONS: Bacillus Calmette-Guerin exerts a direct anti-apoptotic effect on human urothelial carcinoma cell lines. The ability of antibody mediated cross-linking to reproduce the effect and the ability of signal transduction inhibitors to block it are consistent with a mechanism involving integrin mediated signaling. Apoptotic resistance represents a therapeutic target for modulating the response to bacillus Calmette-Guerin and it may have clinical implications in the sequencing of intravesical therapies.
MATERIALS AND METHODS: The human UC cell lines T24 and 253J (American Type Cell Culture, Rockville, Maryland) were used to evaluate the effect of bacillus Calmette-Guerin or antibody mediated alpha5beta1cross-linking on apoptosis and apoptotic sensitivity. Following treatment baseline apoptosis and the response to the apoptotic inducing agent camptothecin was evaluated using assays for caspase 3 activation and DNA fragmentation. Pharmacological blockade of signaling pathways known to be activated in response to bacillus Calmette-Guerin/alpha5beta1 cross-linking was used to assess the role of these pathways in the bacillus Calmette-Guerin apoptotic response. A final series of experiments used the MTT assay to study the impact of bacillus Calmette-Guerin pretreatment on the cytotoxicity of the antineoplastic agent mitomycin C.
RESULTS: Treatment with bacillus Calmette-Guerin failed to induce apoptosis, as measured by caspase 3 activation or DNA laddering. Bacillus Calmette-Guerin pretreatment significantly inhibited the induction of apoptosis in response to camptothecin. These effects were reproduced by antibody mediated cross-linking of alpha5beta1 integrin. Pharmacological inhibition of nuclear factor kappaB and/or AP1 signaling pathways reversed the anti-apoptotic effect of bacillus Calmette-Guerin. Mitomycin C cytotoxicity was significantly decreased by bacillus Calmette-Guerin pretreatment.
CONCLUSIONS: Bacillus Calmette-Guerin exerts a direct anti-apoptotic effect on human urothelial carcinoma cell lines. The ability of antibody mediated cross-linking to reproduce the effect and the ability of signal transduction inhibitors to block it are consistent with a mechanism involving integrin mediated signaling. Apoptotic resistance represents a therapeutic target for modulating the response to bacillus Calmette-Guerin and it may have clinical implications in the sequencing of intravesical therapies.