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

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

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

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

Fingerprint

DNA-(Apurinic or Apyrimidinic Site) Lyase
Endonucleases
Sensory Receptor Cells
Nicorandil
Cisplatin
DNA Damage
Neurons
Chemical activation
Molecules
DNA
Peripheral Nervous System Diseases
Chemotherapy
Drug Therapy
DNA Repair
Repair
Small Molecule Libraries
Aldehyde Dehydrogenase
Platinum
Metabolism
Therapeutics

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

Cite this

Small molecule activation of apurinic/apyrimidinic endonuclease 1 reduces DNA damage induced by cisplatin in cultured sensory neurons. / Georgiadis, Millie; Chen, Qiujia; Meng, Jingwei; Guo, Chunlu; Wireman, Randall; Reed, April; Vasko, Michael; Kelley, Mark.

In: DNA Repair, Vol. 41, 01.05.2016, p. 32-41.

Research output: Contribution to journalArticle

@article{0c722f3984d34a3796e8ad764f3bcd11,
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.",
keywords = "Apurinic/aprymidinic endonuclease 1, Base excision repair, Chemotherapy-induced peripheral neuropathy, Cisplatin, Small molecular activator",
author = "Millie Georgiadis and Qiujia Chen and Jingwei Meng and Chunlu Guo and Randall Wireman and April Reed and Michael Vasko and Mark Kelley",
year = "2016",
month = "5",
day = "1",
doi = "10.1016/j.dnarep.2016.03.009",
language = "English (US)",
volume = "41",
pages = "32--41",
journal = "DNA Repair",
issn = "1568-7864",
publisher = "Elsevier",

}

TY - JOUR

T1 - Small molecule activation of apurinic/apyrimidinic endonuclease 1 reduces DNA damage induced by cisplatin in cultured sensory neurons

AU - Georgiadis, Millie

AU - Chen, Qiujia

AU - Meng, Jingwei

AU - Guo, Chunlu

AU - Wireman, Randall

AU - Reed, April

AU - Vasko, Michael

AU - Kelley, Mark

PY - 2016/5/1

Y1 - 2016/5/1

N2 - 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.

AB - 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.

KW - Apurinic/aprymidinic endonuclease 1

KW - Base excision repair

KW - Chemotherapy-induced peripheral neuropathy

KW - Cisplatin

KW - Small molecular activator

UR - http://www.scopus.com/inward/record.url?scp=84962821141&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84962821141&partnerID=8YFLogxK

U2 - 10.1016/j.dnarep.2016.03.009

DO - 10.1016/j.dnarep.2016.03.009

M3 - Article

C2 - 27078577

AN - SCOPUS:84962821141

VL - 41

SP - 32

EP - 41

JO - DNA Repair

JF - DNA Repair

SN - 1568-7864

ER -