title: Bioenergetic deficits in peripheral nerve sensory axons during chemotherapy-induced neuropathic pain resulting from peroxynitrite-mediated post-translational nitration of mitochondrial superoxide dismutase.
abstract: Many of the widely used anticancer drugs induce dose-limiting peripheral neuropathies that undermine their therapeutic efficacy. Animal models of chemotherapy-induced painful peripheral neuropathy (CIPN) evoked by a variety of drug classes, including taxanes, vinca alkaloids, platinum-complexes, and proteasome-inhibitors, suggest that the common underlying mechanism in the development of these neuropathies is mitotoxicity in primary nerve sensory axons (PNSAs) arising from reduced mitochondrial bioenergetics [eg adenosine triphosphate (ATP) production deficits due to compromised respiratory complex I and II activity]. The causative mechanisms of this mitotoxicity remain poorly defined. However, peroxynitrite, an important pro-nociceptive agent, has been linked to mitotoxicity in several disease states and may also drive the mitotoxicity associated with CIPN. Our findings reveal that the development of mechano-hypersensitivity induced by paclitaxel, oxaliplatin, and bortezomib was prevented by administration of the peroxynitrite decomposition catalyst Mn(III) 5,10,15,20-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin (MnTE-2-PyP(5+)) without interfering with their anti-tumor effects. Peak CIPN was associated with the nitration and inactivation of superoxide dismutase in the mitochondria, but not in the cytosol, as well as a significant decrease in ATP production within the PNSAs; all of these events were attenuated by MnTE-2-PyP(5+). Our results provide continued support for the role of mitotoxicity in the development of CIPN across chemotherapeutic drug classes, and identify peroxynitrite as a key mediator in these processes, thereby providing the rationale towards development of "peroxynitrite-targeted" therapeutics for CIPN.
authors.affiliation: Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, 1402 South Grand Blvd, St. Louis, MO 63104, USA Department of Clinical and Experimental Medicine and Pharmacology, Messina, Italy Department of Pathology, Saint Louis University School of Medicine, 1402 South Grand Blvd, St. Louis, MO 63104, USA Department of Anesthesia, Faculty of Dentistry and Alan Edwards Center for Pain Research, McGill University, Montréal, QC, Canada.
authors.forename: Kali
authors.initials: K
authors.lastname: Janes
authors.forename: Timothy
authors.initials: T
authors.lastname: Doyle
authors.forename: Leesa
authors.initials: L
authors.lastname: Bryant
authors.forename: Emanuela
authors.initials: E
authors.lastname: Esposito
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
authors.forename: Jan
authors.initials: J
authors.lastname: Ryerse
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Bennett
authors.forename: Daniela
authors.initials: D
authors.lastname: Salvemini
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001369:Axons / Q000502:physiology*; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D004734:Energy Metabolism / Q000502:physiology*; D006930:Hyperalgesia / Q000188:drug therapy / Q000523:psychology; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure; D009368:Neoplasm Transplantation; D009437:Neuralgia / Q000139:chemically induced* / Q000378:metabolism*; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D017239:Paclitaxel / Q000494:pharmacology; D010525:Peripheral Nerves / Q000502:physiology*; D030421:Peroxynitrous Acid / Q000502:physiology*; D010812:Physical Stimulation; D011499:Protein Processing, Post-Translational / Q000502:physiology; D011719:Pyrazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000502:physiology*; D013482:Superoxide Dismutase / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D001897:Boronic Acids; D009944:Organoplatinum Compounds; D011719:Pyrazines; D000077150:Oxaliplatin; D030421:Peroxynitrous Acid; D000069286:Bortezomib; D000255:Adenosine Triphosphate; D013482:Superoxide Dismutase; D017239:Paclitaxel
keywords: ATP depletion; Bortezomib; Chemotherapy-induced painful peripheral neuropathy; Mitochondrial dysfunction; Neuropathic pain; Oxaliplatin; Paclitaxel; Peripheral nerve sensory axons; Peroxynitrite; Superoxide dismutase
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