title: Role of the DNA base excision repair protein, APE1 in cisplatin, oxaliplatin, or carboplatin induced sensory neuropathy.
abstract: Although chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of platinum drugs, the mechanisms of this toxicity remain unknown. Previous work in our laboratory suggests that cisplatin-induced CIPN is secondary to DNA damage which is susceptible to base excision repair (BER). To further examine this hypothesis, we studied the effects of cisplatin, oxaliplatin, and carboplatin on cell survival, DNA damage, ROS production, and functional endpoints in rat sensory neurons in culture in the absence or presence of reduced expression of the BER protein AP endonuclease/redox factor-1 (APE1). Using an in situ model of peptidergic sensory neuron function, we examined the effects of the platinum drugs on hind limb capsaicin-evoked vasodilatation. Exposing sensory neurons in culture to the three platinum drugs caused a concentration-dependent increase in apoptosis and cell death, although the concentrations of carboplatin were 10 fold higher than cisplatin. As previously observed with cisplatin, oxaliplatin and carboplatin also increased DNA damage as indicated by an increase in phospho-H2AX and reduced the capsaicin-evoked release of CGRP from neuronal cultures. Both cisplatin and oxaliplatin increased the production of ROS as well as 8-oxoguanine DNA adduct levels, whereas carboplatin did not. Reducing levels of APE1 in neuronal cultures augmented the cisplatin and oxaliplatin induced toxicity, but did not alter the effects of carboplatin. Using an in vivo model, systemic injection of cisplatin (3 mg/kg), oxaliplatin (3 mg/kg), or carboplatin (30 mg/kg) once a week for three weeks caused a decrease in capsaicin-evoked vasodilatation, which was delayed in onset. The effects of cisplatin on capsaicin-evoked vasodilatation were attenuated by chronic administration of E3330, a redox inhibitor of APE1 that serendipitously enhances APE1 DNA repair activity in sensory neurons. These outcomes support the importance of the BER pathway, and particularly APE1, in sensory neuropathy caused by cisplatin and oxaliplatin, but not carboplatin and suggest that augmenting DNA repair could be a therapeutic target for CIPN.
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indianapolis, Indiana, United States of America; Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Kelley
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indianapolis, Indiana, United States of America.
authors.forename: Yanlin
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Chunlu
authors.initials: C
authors.lastname: Guo
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indianapolis, Indiana, United States of America.
authors.forename: April
authors.initials: A
authors.lastname: Reed
authors.affiliation: Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Hongdi
authors.initials: H
authors.lastname: Meng
authors.affiliation: Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Vasko
mesh_terms: D000818:Animals; D016190:Carboplatin / Q000494:pharmacology*; D002478:Cells, Cultured; D002945:Cisplatin / Q000494:pharmacology*; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair / Q000187:drug effects*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000235:genetics*; D051381:Rats; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D016190:Carboplatin; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D002945:Cisplatin