Abstract
The DNA base excision-repair pathway is responsible for the repair of DNA damage caused by oxidation/alkylation and protects cells against the effects of endogenous and exogenous agents. Removal of the damaged base creates a baseless (AP) site. AP endonuclease1 (Ape1) acts on this site to continue the BER-pathway repair. Failure to repair baseless sites leads to DNA strand breaks and cytotoxicity. In addition to the repair role of Ape1, it also functions as a major redox-signaling factor to reduce and activate transcription factors such as AP1, p53, HIF-1alpha, and others that control the expression of genes important for cell survival and cancer promotion and progression. Thus, the Ape1 protein interacts with proteins involved in DNA repair, growth-signaling pathways, and pathways involved in tumor promotion and progression. Although knockdown studies with siRNA have been informative in studying the role of Ape1 in both normal and cancer cells, knocking down Ape1 does not reveal the individual role of the redox or repair functions of Ape1. The identification of small-molecule inhibitors of specific Ape1 functions is critical for mechanistic studies and translational applications. Here we discuss small-molecule inhibition of Ape1 redox and its effect on both cancer and endothelial cells.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Substitution
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Animals
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Benzoquinones / chemical synthesis
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Benzoquinones / pharmacology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cells, Cultured
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DNA Repair / physiology*
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DNA-(Apurinic or Apyrimidinic Site) Lyase / antagonists & inhibitors
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DNA-(Apurinic or Apyrimidinic Site) Lyase / metabolism*
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Endothelial Cells / cytology
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Endothelial Cells / drug effects
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Endothelial Cells / physiology*
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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JNK Mitogen-Activated Protein Kinases / metabolism
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Mice
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Neoplasms / metabolism
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Neoplasms / pathology
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Neoplasms / physiopathology
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Neovascularization, Physiologic / drug effects
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Oxidation-Reduction / drug effects
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Propionates / chemical synthesis
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Propionates / pharmacology
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Retina / cytology
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Transcription Factor AP-1 / genetics
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Transcription Factor AP-1 / metabolism
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Transcriptional Activation / drug effects
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Transfection
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Zebrafish
Substances
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Benzoquinones
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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NF-kappa B
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Propionates
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Transcription Factor AP-1
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E 3330
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JNK Mitogen-Activated Protein Kinases
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APEX1 protein, human
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Apex1 protein, mouse
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DNA-(Apurinic or Apyrimidinic Site) Lyase