title: The Ape-1/Ref-1 redox antagonist E3330 inhibits the growth of tumor endothelium and endothelial progenitor cells: therapeutic implications in tumor angiogenesis.
abstract: The apurinic/apyrimidinic endonuclease 1/redox factor-1 (Ape-1/Ref-1) is a multi-functional protein, involved in DNA repair and the activation of redox-sensitive transcription factors. The Ape-1/Ref-1 redox domain acts as a cytoprotective element in normal endothelial cells, mitigating the deleterious effects of apoptotic stimuli through induction of survival signals. We explored the role of the Ape-1/Ref-1 redox domain in the maintenance of tumor-associated endothelium, and of endothelial progenitor cells (EPCs), which contribute to tumor angiogenesis. We demonstrate that E3330, a small molecule inhibitor of the Ape-1/Ref-1 redox domain, blocks the in vitro growth of pancreatic cancer-associated endothelial cells (PCECs) and EPCs, which is recapitulated by stable expression of a dominant-negative redox domain mutant. Further, E3330 blocks the differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) into CD31(+) endothelial progeny. Exposure of PCECs to E3330 results in a reduction of H-ras expression and intracellular nitric oxide (NO) levels, as well as decreased DNA-binding activity of the hypoxia-inducible transcription factor, HIF-1alpha. E3330 also reduces secreted and intracellular vascular endothelial growth factor expression by pancreatic cancer cells, while concomitantly downregulating the cognate receptor Flk-1/KDR on PCECs. Inhibition of the Ape-1/Ref-1 redox domain with E3330 or comparable angiogenesis inhibitors might be a potent therapeutic strategy in solid tumors.
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA. gzou1@jhmi.edu
authors.forename: Gang-Ming
authors.initials: GM
authors.lastname: Zou
authors.forename: Collins
authors.initials: C
authors.lastname: Karikari
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Kabe
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Handa
authors.forename: Robert A
authors.initials: RA
authors.lastname: Anders
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000378:metabolism*; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology*; D004727:Endothelium / Q000166:cytology / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D009389:Neovascularization, Pathologic; D009569:Nitric Oxide / Q000378:metabolism; D010084:Oxidation-Reduction; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D011422:Propionates / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D016227:Benzoquinones; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011422:Propionates; D042461:Vascular Endothelial Growth Factor A; C075569:E 3330; D009569:Nitric Oxide; D040301:Vascular Endothelial Growth Factor Receptor-2; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase