Antitumor Activity and Mechanistic Characterization of APE1/Ref-1 Inhibitors in Bladder Cancer.

Abstract

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.

• Authors: Melissa L Fishel, Hanyu Xia, Jack McGeown, David W McIlwain, May Elbanna, Ariel A Craft, Hristos Z Kaimakliotis, George E Sandusky, Chi Zhang, Roberto Pili, Mark R Kelley, Travis J Jerde
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 18 Issue 11 Pg. 1947-1960 (11 2019) ISSN: 1538-8514 [Electronic] United States
• PMID: 31413178 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Benzoquinones
• Propionates
• E 3330
• APEX1 protein, human
• DNA-(Apurinic or Apyrimidinic Site) Lyase
• Cisplatin

Topics

• Aged
• Animals
• Benzoquinones (administration & dosage, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cisplatin (administration & dosage, pharmacology)
• DNA-(Apurinic or Apyrimidinic Site) Lyase (antagonists & inhibitors, genetics)
• Drug Synergism
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Male
• Mice
• Middle Aged
• Propionates (administration & dosage, pharmacology)
• Up-Regulation (drug effects)
• Urinary Bladder Neoplasms (drug therapy, metabolism)
• Xenograft Model Antitumor Assays