title: Small molecule activation of apurinic/apyrimidinic endonuclease 1 reduces DNA damage induced by cisplatin in cultured sensory neurons.
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 kcat. 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, United States; Department of Chemistry and Chemical Biology, Indiana University Purdue University at Indianapolis, Indianapolis, IN, United States. Electronic address: mgeorgia@iu.edu.
authors.forename: Millie M
authors.initials: MM
authors.lastname: Georgiadis
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, United States.
authors.forename: Qiujia
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, United States.
authors.forename: Jingwei
authors.initials: J
authors.lastname: Meng
authors.affiliation: Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, United States.
authors.forename: Chunlu
authors.initials: C
authors.lastname: Guo
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States.
authors.forename: Randall
authors.initials: R
authors.lastname: Wireman
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States.
authors.forename: April
authors.initials: A
authors.lastname: Reed
authors.affiliation: Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, United States.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Vasko
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, United States; Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, United States; Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Kelley
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002945:Cisplatin / Q000009:adverse effects*; D004249:DNA Damage; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism*; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology; D008297:Male; D020108:Nicorandil / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007529:Isoflavones; D020108:Nicorandil; C013908:daidzin; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D002945:Cisplatin
keywords: Apurinic/aprymidinic endonuclease 1; Base excision repair; Chemotherapy-induced peripheral neuropathy; Cisplatin; Small molecular activator