title: Prevention of chemotherapy-induced peripheral neuropathy by the small-molecule inhibitor pifithrin-μ.
abstract: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of cancer treatment. It is the most frequent cause of dose reduction or treatment discontinuation in patients treated for cancer with commonly used drugs including taxanes and platinum-based compounds. No FDA-approved treatments for CIPN are available. In rodents, CIPN is represented by peripheral mechanical allodynia in association with retraction of intraepidermal nerve fibers. The mechanism of chemotherapy-induced neurotoxicity is unclear, but it has been established that mitochondrial dysfunction is an important component of the dysregulation in peripheral sensory neurons. We have shown earlier that inhibition of mitochondrial p53 accumulation with the small compound pifithrin-μ (PFT-μ) prevents cerebral neuronal death in a rodent model of hypoxic-ischemic brain damage. We now explore whether PFT-μ is capable of preventing neuronal mitochondrial damage and CIPN in mice. We demonstrate for the first time that PFT-μ prevents both paclitaxel- and cisplatin-induced mechanical allodynia. Electron microscopic analysis of peripheral sensory nerves revealed that PFT-μ secured mitochondrial integrity in paclitaxel-treated mice. In addition, PFT-μ administration protects against chemotherapy-induced loss of intraepidermal nerve fibers in the paw. To determine whether neuroprotective treatment with PFT-μ would interfere with the antitumor effects of chemotherapy, ovarian tumor cells were cultured in vitro with PFT-μ and paclitaxel. Pifithrin-μ does not inhibit tumor cell death but even enhances paclitaxel-induced tumor cell death. These data are the first to identify PFT-μ as a potential therapeutic strategy for prevention of CIPN to combat one of the most devastating side effects of chemotherapy.
authors.affiliation: Laboratory of Neuroimmunology, Department Symptom Research, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Laboratory of Neuroimmunology and Developmental Origins of Disease (NIDOD), University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Karen
authors.initials: K
authors.lastname: Krukowski
authors.forename: Cora H
authors.initials: CH
authors.lastname: Nijboer
authors.forename: XiaoJiao
authors.initials: X
authors.lastname: Huo
authors.forename: Annemieke
authors.initials: A
authors.lastname: Kavelaars
authors.forename: Cobi J
authors.initials: CJ
authors.lastname: Heijnen
mesh_terms: D000700:Analgesics / Q000627:therapeutic use*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects*; D002945:Cisplatin / Q000633:toxicity; D004195:Disease Models, Animal; D005260:Female; D005727:Ganglia, Spinal / Q000473:pathology; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000473:pathology / Q000648:ultrastructure; D017239:Paclitaxel / Q000009:adverse effects*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D013449:Sulfonamides / Q000627:therapeutic use*; D043222:Ubiquitin Thiolesterase / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C545747:2-phenylacetylenesulfonamide; D000700:Analgesics; D000972:Antineoplastic Agents, Phytogenic; D013449:Sulfonamides; D043222:Ubiquitin Thiolesterase; C496976:Uchl1 protein, mouse; D017239:Paclitaxel; D002945:Cisplatin