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: Gang-Ming Zou, Collins Karikari, Yasuaki Kabe, Hiroshi Handa, Robert A Anders, Anirban Maitra
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 219 Issue 1 Pg. 209-18 (Apr 2009) ISSN: 1097-4652 [Electronic] United States
• PMID: 19097035 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2008 Wiley-Liss, Inc.

Chemical References

• Benzoquinones
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Propionates
• Vascular Endothelial Growth Factor A
• E 3330
• Nitric Oxide
• Vascular Endothelial Growth Factor Receptor-2
• APEX1 protein, human
• DNA-(Apurinic or Apyrimidinic Site) Lyase

Topics

• Animals
• Benzoquinones (metabolism)
• Cell Differentiation
• Cell Lineage
• Cells, Cultured
• DNA-(Apurinic or Apyrimidinic Site) Lyase (antagonists & inhibitors, genetics, metabolism)
• Endothelial Cells (cytology, physiology)
• Endothelium (cytology, physiology)
• Homeostasis
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Male
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Neoplasms (drug therapy, pathology, physiopathology)
• Neovascularization, Pathologic
• Nitric Oxide (metabolism)
• Oxidation-Reduction
• Pancreatic Neoplasms (drug therapy, pathology, physiopathology)
• Propionates (metabolism)
• Stem Cells (cytology, physiology)
• Transplantation, Heterologous
• Vascular Endothelial Growth Factor A (metabolism)
• Vascular Endothelial Growth Factor Receptor-2 (metabolism)