Functional analysis of novel analogues of E3330 that block the redox signaling activity of the multifunctional AP endonuclease/redox signaling enzyme APE1/Ref-1

Mark Kelley, Meihua Luo, April Reed, Dian Su, Sarah Delaplane, Richard F. Borch, Rodney L. Nyland, Michael L. Gross, Millie Georgiadis

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

APE1 is a multifunctional protein possessing DNA repair and redox activation of transcription factors. Blocking these functions leads to apoptosis, antiangiogenesis, cell-growth inhibition, and other effects, depending on which function is blocked. Because a selective inhibitor of the APE redox function has potential as a novel anticancer therapeutic, new analogues of E3330 were synthesized. Mass spectrometry was used to characterize the interactions of the analogues (RN8-51, 10-52, and 7-60) with APE1. RN10-52 and RN7-60 were found to react rapidly with APE1, forming covalent adducts, whereas RN8-51 reacted reversibly. Median inhibitory concentration (IC 50 values of all three compounds were significantly lower than that of E3330. EMSA, transactivation assays, and endothelial tube growth-inhibition analysis demonstrated the specificity of E3330 and its analogues in blocking the APE1 redox function and demonstrated that the analogues had up to a sixfold greater effect than did E3330. Studies using cancer cell lines demonstrated that E3330 and one analogue, RN8-51, decreased the cell line growth with little apoptosis, whereas the third, RN7-60, caused a dramatic effect. RN8-51 shows particular promise for further anticancer therapeutic development. This progress in synthesizing and isolating biologically active novel E3330 analogues that effectively inhibit the APE1 redox function validates the utility of further translational anticancer therapeutic development.

Original languageEnglish
Pages (from-to)1387-1401
Number of pages15
JournalAntioxidants and Redox Signaling
Volume14
Issue number8
DOIs
StatePublished - Apr 15 2011

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DNA-(Apurinic or Apyrimidinic Site) Lyase
Functional analysis
Oxidation-Reduction
Enzymes
Growth
Cells
Apoptosis
Cell Line
Cell growth
DNA Repair
Transcriptional Activation
Inhibitory Concentration 50
Mass spectrometry
E 3330
Assays
Mass Spectrometry
Repair
Transcription Factors
Therapeutics
Chemical activation

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Physiology
  • Clinical Biochemistry

Cite this

Functional analysis of novel analogues of E3330 that block the redox signaling activity of the multifunctional AP endonuclease/redox signaling enzyme APE1/Ref-1. / Kelley, Mark; Luo, Meihua; Reed, April; Su, Dian; Delaplane, Sarah; Borch, Richard F.; Nyland, Rodney L.; Gross, Michael L.; Georgiadis, Millie.

In: Antioxidants and Redox Signaling, Vol. 14, No. 8, 15.04.2011, p. 1387-1401.

Research output: Contribution to journalArticle

Kelley, Mark ; Luo, Meihua ; Reed, April ; Su, Dian ; Delaplane, Sarah ; Borch, Richard F. ; Nyland, Rodney L. ; Gross, Michael L. ; Georgiadis, Millie. / Functional analysis of novel analogues of E3330 that block the redox signaling activity of the multifunctional AP endonuclease/redox signaling enzyme APE1/Ref-1. In: Antioxidants and Redox Signaling. 2011 ; Vol. 14, No. 8. pp. 1387-1401.
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