PT  - JOURNAL ARTICLE
AU  - Fishel, Melissa L.
AU  - Xia, Hanyu
AU  - McGeown, Jack
AU  - McIlwain, David W.
AU  - Elbanna, May
AU  - Craft, Ariel A.
AU  - Kaimakliotis, Hristos Z.
AU  - Sandusky, George E.
AU  - Zhang, Chi
AU  - Pili, Roberto
AU  - Kelley, Mark R.
AU  - Jerde, Travis J.
TI  - Antitumor Activity and Mechanistic Characterization of APE1/Ref-1 Inhibitors in Bladder Cancer
AID  - 10.1158/1535-7163.MCT-18-1166
DP  - 2019 Nov 01
TA  - Molecular Cancer Therapeutics
PG  - 1947--1960
VI  - 18
IP  - 11
4099  - http://mct.aacrjournals.org/content/18/11/1947.short
4100  - http://mct.aacrjournals.org/content/18/11/1947.full
SO  - Mol Cancer Ther2019 Nov 01; 18
AB  - Bladder 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.