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Article

Intravesical Instillation of Azacitidine Suppresses Tumor Formation through TNF-R1 and TRAIL-R2 Signaling in Genotoxic Carcinogen-Induced Bladder Cancer

1
Department of Urology, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
2
School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
3
Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
*
Author to whom correspondence should be addressed.
Academic Editor: Andrea Morrione
Cancers 2021, 13(16), 3933; https://doi.org/10.3390/cancers13163933
Received: 18 June 2021 / Revised: 31 July 2021 / Accepted: 2 August 2021 / Published: 4 August 2021
Approximately 70% of all bladder cancer is diagnosed as non-muscle invasive bladder cancer and can be treated by transurethral resection of the bladder tumor, followed by intravesical instillation chemotherapy. Bacille Calmette-Guérin (BCG) is the first-line agent for intravesical instillation, but its accessibility has been limited for years due to a BCG shortage. Here, our aim was to evaluate the therapeutic role of intravesical instillation of azacitidine, a DNA methyltransferase inhibitor, in bladder cancer. Cell model experiments showed that azacitidine inhibited TNFR1 downstream pathways to downregulate HIF-1α, claspin, and survivin. Concomitant upregulation of the TRAIL R2 pathway by azacitidine ultimately drove the tumor cells to apoptosis. Rats with genotoxic carcinogen-induced bladder cancer showed a significantly reduced in vivo tumor burden after intravesical instillation of azacitidine. These findings might support further clinical trials of azacitidine in bladder cancer.
Azacitidine, an inhibitor of DNA methylation, shows therapeutic effects against several malignancies by inducing apoptosis and inhibiting tumor cell proliferation. However, the anti-tumor effects of azacitidine on urinary bladder urothelial carcinoma (UBUC), especially following intravesical instillation (IVI), are not established. Here, UBUC cell lines were used to analyze the in vitro therapeutic effects of azacitidine. Potential signaling pathways were investigated by antibody arrays and Western blotting. The N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced rat UBUC model was used for in vivo quantitative analysis of tumor burden. Azacitidine significantly inhibited DNMT expression in UBUC cell lines and reduced cell viability and clonogenic activity, as determined by MTT and colony formation assays, while also inducing significant cytotoxic effects in the form of increased sub-G1 and Annexin V-PI populations (all p < 0.05). Antibody arrays confirmed the in vitro suppression of TNF-R1 and the induction of TRAIL-R2 and their downstream signaling molecules. TNF-R1 suppression reduced claspin and survivin expression, while TRAIL-R2 activation induced cytochrome C and caspase 3 expression. Rats with BBN-induced bladder cancer had a significantly reduced tumor burden and Ki67 index following IVI of azacitidine (p < 0.01). Our study provides evidence for a reduction in BBN-induced bladder cancer by IVI of azacitidine through alterations in the TRAIL-R2 and TNF-R1 signaling pathways. These findings might provide new insights for further clinical trials. View Full-Text
Keywords: bladder cancer; azacitidine; intravesical instillation; TNF-R1; TRAIL-R2 bladder cancer; azacitidine; intravesical instillation; TNF-R1; TRAIL-R2
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MDPI and ACS Style

Wang, S.-C.; Chang, Y.-C.; Wu, M.-Y.; Yu, C.-Y.; Chen, S.-L.; Sung, W.-W. Intravesical Instillation of Azacitidine Suppresses Tumor Formation through TNF-R1 and TRAIL-R2 Signaling in Genotoxic Carcinogen-Induced Bladder Cancer. Cancers 2021, 13, 3933. https://doi.org/10.3390/cancers13163933

AMA Style

Wang S-C, Chang Y-C, Wu M-Y, Yu C-Y, Chen S-L, Sung W-W. Intravesical Instillation of Azacitidine Suppresses Tumor Formation through TNF-R1 and TRAIL-R2 Signaling in Genotoxic Carcinogen-Induced Bladder Cancer. Cancers. 2021; 13(16):3933. https://doi.org/10.3390/cancers13163933

Chicago/Turabian Style

Wang, Shao-Chuan, Ya-Chuan Chang, Min-You Wu, Chia-Ying Yu, Sung-Lang Chen, and Wen-Wei Sung. 2021. "Intravesical Instillation of Azacitidine Suppresses Tumor Formation through TNF-R1 and TRAIL-R2 Signaling in Genotoxic Carcinogen-Induced Bladder Cancer" Cancers 13, no. 16: 3933. https://doi.org/10.3390/cancers13163933

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