Abstract 5285: Antitumor and mechanism of selective serotonin reuptake inhibitor fluoxetine on muscle invasive bladder cancer

Abstract Purpose/Introduction: Bladder cancer can be broadly divided into two type, including non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC). Among them, MIBC has been recognized as hard to treatment type of cancer for many decades. Therefore, to develop a new treatment strategy for MIBC is urgently needed. Transcription factor nuclear factor-kappaB (NF-κB) plays important role in various cancer progression, including hepatocellular carcinoma (HCC), lung adenocarcinoma (LUAD), and MIBC. Thus, NF-κB may be a potential target to suppress the progression of MIBC. Fluoxetine is FDA approval antidepressant agent, belongs to selective serotonin reuptake inhibitor (SSRI). Interestingly, recent study indicated that Fluoxetine inhibited NF-κB and induced apoptosis in the HCC both in vivo and in vitro. However, whether Fluoxetine may regulate NF-κB and inhibit MIBC tumor progression is remaining unknown. Therefore, the aim of present study is to verify the treatment efficacy and underlying mechanism of fluoxetine on MIBC. Methods: Human MIBC cells TSGH8301 and T24 cells and mice bearing with MIBC MB49 cells was used in this study. Cytotoxicity, apoptosis, and metastasis ability of cells after fluoxetine treatment was validated through MTT assay, cleaved caspase-3, -8, -9 activation using flow cytometry and transwell migration/invasion assay, respectively. In in vivo study murine MB49 cells were subcutaneous inoculated into right flank of C57B6/J mice and treated with fluoxetine for 15 days. Result: Fluoxetine markedly induced cytotoxicity, cleaved caspase-3, -8, -9 expression, and inhibited migration and invasion in both TSGH8301 and T24 cells. Western blotting and reporter gene assay indicated that fluoxetine may suppress the phosphorylation and activity of NF-κB. In in vivo results, fluoxetine inhibited tumor growth and the expression of NF-κB within tumor. Tumor immunohistochemistry (IHC) staining results proved that the apoptosis marker such as Caspase-3, -8, -9 were all increased by fluoxetine. AST and ALT value that represent as liver function showed no significant difference between vehicle group and fluoxetine treatment group. Body weight and H&E results also proved the safety of fluoxetine usage. Conclusion: Fluoxetine induced cytotoxicity via both extrinsic/intrinsic apoptotic pathway and inhibited metastasis ability as well. Fluoxetine may also suppress the phosphorylation and activity NF-κB in vitro and in vivo. In sum, we suggested that fluoxetine may effectively suppress tumor progression via inactivate NF-κB signaling pathway. Citation Format: Zhao-Lin Tan, Yuan Chang, I-Tsang Chiang, Fei-Ting Hsu, Fei-Ting Hsu. Antitumor and mechanism of selective serotonin reuptake inhibitor fluoxetine on muscle invasive bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5285.