The Ape-1/Ref-1 redox antagonist E3330 inhibits the growth of tumor endothelium and endothelial progenitor cells

therapeutic implications in tumor angiogenesis

Gang Ming Zou, Collins Karikari, Yasuaki Kabe, Hiroshi Handa, Robert A. Anders, Anirban Maitraz

Research output: Contribution to journalArticle

53 Citations (Scopus)

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-1α. 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.

Original languageEnglish
Pages (from-to)209-218
Number of pages10
JournalJournal of Cellular Physiology
Volume219
Issue number1
DOIs
Publication statusPublished - 2009 Apr
Externally publishedYes

Fingerprint

Endothelial cells
Hominidae
Oxidation-Reduction
Endothelium
Tumors
Pancreatic Neoplasms
Growth
Endothelial Cells
Neoplasms
Therapeutics
Transcription Factors
DNA-(Apurinic or Apyrimidinic Site) Lyase
Angiogenesis Inhibitors
Endonucleases
DNA
Endothelial Progenitor Cells
E 3330
Stem cells
Mesenchymal Stromal Cells
DNA Repair

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

Cite this

The Ape-1/Ref-1 redox antagonist E3330 inhibits the growth of tumor endothelium and endothelial progenitor cells : therapeutic implications in tumor angiogenesis. / Zou, Gang Ming; Karikari, Collins; Kabe, Yasuaki; Handa, Hiroshi; Anders, Robert A.; Maitraz, Anirban.

In: Journal of Cellular Physiology, Vol. 219, No. 1, 04.2009, p. 209-218.

Research output: Contribution to journalArticle

Zou, Gang Ming ; Karikari, Collins ; Kabe, Yasuaki ; Handa, Hiroshi ; Anders, Robert A. ; Maitraz, Anirban. / The Ape-1/Ref-1 redox antagonist E3330 inhibits the growth of tumor endothelium and endothelial progenitor cells : therapeutic implications in tumor angiogenesis. In: Journal of Cellular Physiology. 2009 ; Vol. 219, No. 1. pp. 209-218.
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