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 | Kali Janes, Timothy Doyle, Leesa Bryant, Emanuela Esposito, Salvatore Cuzzocrea, Jan Ryerse, Gary J Bennett, Daniela Salvemini |
Journal | Pain
(Pain)
Vol. 154
Issue 11
Pg. 2432-2440
(Nov 2013)
ISSN: 1872-6623 [Electronic] United States |
PMID | 23891899
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Copyright | Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. |
Chemical References |
- Antineoplastic Agents
- Antineoplastic Agents, Phytogenic
- Boronic Acids
- Organoplatinum Compounds
- Pyrazines
- Oxaliplatin
- Peroxynitrous Acid
- Bortezomib
- Adenosine Triphosphate
- Superoxide Dismutase
- Paclitaxel
|
Topics |
- Adenosine Triphosphate
(metabolism)
- Animals
- Antineoplastic Agents
(adverse effects, pharmacology)
- Antineoplastic Agents, Phytogenic
(pharmacology)
- Axons
(physiology)
- Boronic Acids
(pharmacology)
- Bortezomib
- Energy Metabolism
(physiology)
- Hyperalgesia
(drug therapy, psychology)
- Male
- Mitochondria
(drug effects, ultrastructure)
- Neoplasm Transplantation
- Neuralgia
(chemically induced, metabolism)
- Organoplatinum Compounds
(pharmacology)
- Oxaliplatin
- Paclitaxel
(pharmacology)
- Peripheral Nerves
(physiology)
- Peroxynitrous Acid
(physiology)
- Physical Stimulation
- Protein Processing, Post-Translational
(physiology)
- Pyrazines
(pharmacology)
- Rats
- Rats, Sprague-Dawley
- Sensory Receptor Cells
(physiology)
- Superoxide Dismutase
(metabolism)
|