title: Mitotoxicity and bortezomib-induced chronic painful peripheral neuropathy.
abstract: Many of the most effective anti-cancer drugs induce a dose-limiting peripheral neuropathy that compromises therapy. Evidence from animal models of chemotherapy-induced painful peripheral neuropathy produced by the taxane agent, paclitaxel, and the platinum-complex agent, oxaliplatin, indicate that they produce neuropathy via a common mechanism-a toxic effect on the mitochondria in primary afferent sensory neurons. Bortezomib is from the proteasome-inhibitor class of chemotherapeutics. It also produces a dose-limiting peripheral neuropathy, but its effects on neuronal mitochondria are unknown. To investigate this, we developed a model of bortezomib-induced painful peripheral neuropathy in the rat and assessed mitochondrial function (respiration and ATP production) in sciatic nerve samples harvested at two time points: day 7, which is three days after treatment and before pain appears, and day 35, which is one month post-treatment and the time of peak pain severity. We found significant deficits in Complex I-mediated and Complex II-mediated respiration, and in ATP production at both time points. Prophylactic treatment with acetyl-L-carnitine, which has previously been shown to prevent paclitaxel- and oxaliplatin-induced mitochondrial dysfunction and pain, completely blocked bortezomib's effects on mitochondria and pain. These results suggest that mitotoxicity may be the core pathology for all chemotherapy-induced peripheral neuropathy and that drugs that protect mitochondrial function may be useful chemotherapy adjuncts.
authors.affiliation: Department of Anesthesia, McGill University, Montréal, QC, Canada.
authors.forename: H
authors.initials: H
authors.lastname: Zheng
authors.forename: W H
authors.initials: WH
authors.lastname: Xiao
authors.forename: G J
authors.initials: GJ
authors.lastname: Bennett
mesh_terms: D000108:Acetylcarnitine / Q000627:therapeutic use; D051700:Activating Transcription Factor 3 / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001369:Axons / Q000187:drug effects / Q000473:pathology; D001897:Boronic Acids / Q000633:toxicity*; D000069286:Bortezomib; D002950:Citrate (si)-Synthase / Q000378:metabolism; D004195:Disease Models, Animal; D042963:Electron Transport Complex II / Q000378:metabolism; D005727:Ganglia, Spinal / Q000473:pathology; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology*; D010146:Pain / Q000188:drug therapy / Q000209:etiology; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000150:complications / Q000473:pathology*; D011719:Pyrazines / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012583:Schwann Cells / Q000473:pathology / Q000648:ultrastructure; D012584:Sciatic Nerve / Q000503:physiopathology; D013997:Time Factors; D043222:Ubiquitin Thiolesterase / Q000378:metabolism
chemical_list: D051700:Activating Transcription Factor 3; D000970:Antineoplastic Agents; C497108:Atf3 protein, rat; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D000108:Acetylcarnitine; D000255:Adenosine Triphosphate; D042963:Electron Transport Complex II; D002950:Citrate (si)-Synthase; C489034:UCHL1 protein, rat; D043222:Ubiquitin Thiolesterase