title: Impact of APE1/Ref-1 redox inhibition on pancreatic tumor growth.
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.
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University of School of Medicine, 980 W. Walnut, R3-548, Indianapolis, IN 46202, USA. mfishel@iupui.edu
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Fishel
authors.forename: Yanlin
authors.initials: Y
authors.lastname: Jiang
authors.forename: N V
authors.initials: NV
authors.lastname: Rajeshkumar
authors.forename: Glenda
authors.initials: G
authors.lastname: Scandura
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Sinn
authors.forename: Ying
authors.initials: Y
authors.lastname: He
authors.forename: Changyu
authors.initials: C
authors.lastname: Shen
authors.forename: David R
authors.initials: DR
authors.lastname: Jones
authors.forename: Karen E
authors.initials: KE
authors.lastname: Pollok
authors.forename: Mircea
authors.initials: M
authors.lastname: Ivan
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.forename: Mark R
authors.initials: MR
authors.lastname: Kelley
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D016328:NF-kappa B / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000201:enzymology*; D011422:Propionates / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D016227:Benzoquinones; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D011422:Propionates; C075569:E 3330; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase