Antitumor activity and mechanistic characterization of APE1/ReF-1 inhibitors in bladder cancer

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

Research output: Contribution to journalArticle

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-kB 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.

Original languageEnglish (US)
Pages (from-to)1947-1960
Number of pages14
JournalMolecular cancer therapeutics
Volume18
Issue number11
DOIs
StatePublished - Jan 1 2019

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Endonucleases
Urinary Bladder Neoplasms
Oxidation-Reduction
Cisplatin
Cell Proliferation
DNA-(Apurinic or Apyrimidinic Site) Lyase
Urothelium
STAT3 Transcription Factor
NF-kappa B
Cyclin D1
Standard of Care
DNA Repair
Immunotherapy
Neoplasms
Transcription Factors
Therapeutics
Apoptosis
Drug Therapy
Survival
Growth

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Antitumor activity and mechanistic characterization of APE1/ReF-1 inhibitors in bladder cancer. / Fishel, Melissa L.; Xia, Hanyu; McGeown, Jack; McIlwain, David W.; Elbanna, May; Craft, Ariel A.; Kaimakliotis, Hristos Z.; Sandusky, George E.; Zhang, Chi; Pili, Roberto; Kelley, Mark R.; Jerde, Travis J.

In: Molecular cancer therapeutics, Vol. 18, No. 11, 01.01.2019, p. 1947-1960.

Research output: Contribution to journalArticle

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