Fishel, Melissa L.Xia, HanyuMcGeown, JackMcIlwain, David W.Elbanna, MayCraft, Ariel A.Kaimakliotis, Hristos Z.Sandusky, George E.Zhang, ChiPili, RobertoKelley, Mark R.Jerde, Travis J.2020-07-302020-07-302019-08-14Fishel, M. L., Xia, H., McGeown, J., McIlwain, D. W., Elbanna, M., Craft, A. A., Kaimakliotis, H. Z., Sandusky, G. E., Zhang, C., Pili, R., Kelley, M. R., & Jerde, T. J. (2019). Antitumor Activity and Mechanistic Characterization of APE1/Ref-1 Inhibitors in Bladder Cancer. Molecular cancer therapeutics, 18(11), 1947–1960. https://doi.org/10.1158/1535-7163.MCT-18-1166https://hdl.handle.net/1805/23446Bladder cancer is the ninth most common cause of cancer-related deaths worldwide. Although cisplatin is used routinely in treating bladder cancer, refractory disease remains lethal for many patients. The recent addition of immunotherapy has improved patient outcomes; however, a large cohort of patients does not respond to these treatments. Therefore, identification of innovative molecular targets for bladder cancer is crucial. Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a multifunctional protein involved in both DNA repair and activation of transcription factors through reduction-oxidation (redox) regulation. High APE1/Ref-1 expression is associated with shorter patient survival time in many cancer types. In this study, we found high APE1/Ref-1 expression in human bladder cancer tissue relative to benign urothelium. Inhibition of APE1/Ref-1 redox signaling using APE1/Ref-1-specific inhibitors attenuates bladder cancer cell proliferation in monolayer, in three-dimensional cultures, and in vivo. This inhibition corresponds with an increase in apoptosis and decreased transcriptional activity of NF-κB and STAT3, transcription factors known to be regulated by APE1/Ref-1, resulting in decreased expression of downstream effectors survivin and Cyclin D1 in vitro and in vivo. We also demonstrate that in vitro treatment of bladder cancer cells with APE1/Ref-1 redox inhibitors in combination with standard-of-care chemotherapy cisplatin is more effective than cisplatin alone at inhibiting cell proliferation. Collectively, our data demonstrate that APE1/Ref-1 is a viable drug target for the treatment of bladder cancer, provide a mechanism of APE1/Ref-1 action in bladder cancer cells, and support the use of novel redox-selective APE1/Ref-1 inhibitors in clinical studies. SIGNIFICANCE: This work identifies a critical mechanism for APE1/Ref-1 in bladder cancer growth and provides compelling preclinical data using selective redox activity inhibitors of APE1/Ref-1 in vitro and in vivo.en-USPublisher PolicyBladder cancerAPE1/Ref-1STAT3 signalingNFκB signalingRedox regulationArticle