Impact of APE1/ref-1 redox inhibition on pancreatic tumor growth

Melissa L. Fishel, Yanlin Jiang, N. V. Rajeshkumar, Glenda Scandura, Anthony L. Sinn, Ying He, Changyu Shen, David R. Jones, Karen E. Pollok, Mircea Ivan, Anirban Maitra, Mark R. Kelley

Research output: Contribution to journalArticle

52 Scopus citations

Abstract

Pancreatic cancer is especially a deadly form of cancer with a survival rate less than 2%. Pancreatic cancers respond poorly to existing chemotherapeutic agents and radiation, and progress for the treatment of pancreatic cancer remains elusive. To address this unmet medical need, a better understanding of critical pathways and molecular mechanisms involved in pancreatic tumor development, progression, and resistance to traditional therapy is therefore critical. Reduction-oxidation (redox) signaling systems are emerging as important targets in pancreatic cancer. AP endonuclease1/Redox effector factor 1 (APE1/Ref-1) is upregulated in human pancreatic cancer cells and modulation of its redox activity blocks the proliferation and migration of pancreatic cancer cells and pancreatic cancer-associated endothelial cells in vitro. Modulation of APE1/Ref-1 using a specific inhibitor of APE1/Ref-1's redox function, E3330, leads to a decrease in transcription factor activity for NFκB, AP-1, and HIF1α in vitro. This study aims to further establish the redox signaling protein APE1/Ref-1 as a molecular target in pancreatic cancer. Here, we show that inhibition of APE1/Ref-1 via E3330 results in tumor growth inhibition in cell lines and pancreatic cancer xenograft models in mice. Pharmacokinetic studies also show that E3330 attains more than10 μmol/L blood concentrations and is detectable in tumor xenografts. Through inhibition of APE1/Ref-1, the activity of NFκB, AP-1, and HIF1α that are key transcriptional regulators involved in survival, invasion, and metastasis is blocked. These data indicate that E3330, inhibitor of APE1/Ref-1, has potential in pancreatic cancer and clinical investigation of APE1/Ref-1 molecular target is warranted.

Original languageEnglish (US)
Pages (from-to)1698-1708
Number of pages11
JournalMolecular cancer therapeutics
Volume10
Issue number9
DOIs
StatePublished - Sep 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Fishel, M. L., Jiang, Y., Rajeshkumar, N. V., Scandura, G., Sinn, A. L., He, Y., Shen, C., Jones, D. R., Pollok, K. E., Ivan, M., Maitra, A., & Kelley, M. R. (2011). Impact of APE1/ref-1 redox inhibition on pancreatic tumor growth. Molecular cancer therapeutics, 10(9), 1698-1708. https://doi.org/10.1158/1535-7163.MCT-11-0107