Small molecule activation of apurinic/apyrimidinic endonuclease 1 reduces DNA damage induced by cisplatin in cultured sensory neurons

Millie M. Georgiadis, Qiujia Chen, Jingwei Meng, Chunlu Guo, Randall Wireman, April Reed, Michael R. Vasko, Mark R. Kelley

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Although chemotherapy-induced peripheral neuropathy (CIPN) affects approximately 5-60% of cancer patients, there are currently no treatments available in part due to the fact that the underlying causes of CIPN are not well understood. One contributing factor in CIPN may be persistence of DNA lesions resulting from treatment with platinum-based agents such as cisplatin. In support of this hypothesis, overexpression of the base excision repair (BER) enzyme, apurinic/apyrimidinic endonuclease 1 (APE1), reduces DNA damage and protects cultured sensory neurons treated with cisplatin. Here, we address stimulation of APE1's endonuclease through a small molecule, nicorandil, as a means of mimicking the beneficial effects observed for overexpression of APE1. Nicorandil, was identified through high-throughput screening of small molecule libraries and found to stimulate APE1 endonuclease activity by increasing catalytic efficiency approximately 2-fold. This stimulation is primarily due to an increase in k cat . To prevent metabolism of nicorandil, an approved drug in Europe for the treatment of angina, cultured sensory neurons were pretreated with nicorandil and daidzin, an aldehyde dehydrogenase 2 inhibitor, resulting in decreased DNA damage but not altered transmitter release by cisplatin. This finding suggests that activation of APE1 by nicorandil in cisplatin-treated cultured sensory neurons does not imbalance the BER pathway in contrast to overexpression of the kinetically faster R177A APE1. Taken together, our results suggest that APE1 activators can be used to reduce DNA damage induced by cisplatin in cultured sensory neurons, although further studies will be required to fully assess their protective effects.

Original languageEnglish (US)
Pages (from-to)32-41
Number of pages10
JournalDNA Repair
Volume41
DOIs
StatePublished - May 1 2016

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Keywords

  • Apurinic/aprymidinic endonuclease 1
  • Base excision repair
  • Chemotherapy-induced peripheral neuropathy
  • Cisplatin
  • Small molecular activator

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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