Novel therapeutic strategy to prevent chemotherapy-induced persistent sensory neuropathy by TRPA1 blockade.

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a severe and painful adverse reaction of cancer treatment in patients that is little understood or treated. Cytotoxic drugs that cause CIPN exert their effects by increasing oxidative stress, which activates the ion channel TRPA1 expressed by nociceptors. In this study, we evaluated whether TRPA1 acted as a critical mediator of CIPN by bortezomib or oxaliplatin in a mouse model system. Bortezomib evoked a prolonged mechanical, cold, and selective chemical hypersensitivity (the latter against the TRPA1 agonist allyl isothiocyanate). This CIPN hypersensitivity phenotype that was stably established by bortezomib could be transiently reverted by systemic or local treatment with the TRPA1 antagonist HC-030031. A similar effect was produced by the oxidative stress scavenger α-lipoic acid. Notably, the CIPN phenotype was abolished completely in mice that were genetically deficient in TRPA1, highlighting its essential role. Administration of bortezomib or oxaliplatin, which also elicits TRPA1-dependent hypersensitivity, produced a rapid, transient increase in plasma of carboxy-methyl-lysine, a by-product of oxidative stress. Short-term systemic treatment with either HC-030031 or α-lipoic acid could completely prevent hypersensitivity if administered before the cytotoxic drug. Our findings highlight a key role for early activation/sensitization of TRPA1 by oxidative stress by-products in producing CIPN. Furthermore, they suggest prevention strategies for CIPN in patients through the use of early, short-term treatments with TRPA1 antagonists.

• Authors: Gabriela Trevisan, Serena Materazzi, Camilla Fusi, Alessandra Altomare, Giancarlo Aldini, Maura Lodovici, Riccardo Patacchini, Pierangelo Geppetti, Romina Nassini
• Journal: Cancer research (Cancer Res) Vol. 73 Issue 10 Pg. 3120-31 (May 15 2013) ISSN: 1538-7445 [Electronic] United States
• PMID: 23477783 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2013 AACR.

Chemical References

• 2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide
• Acetanilides
• Antineoplastic Agents
• Boronic Acids
• Organoplatinum Compounds
• Purines
• Pyrazines
• TRPA1 Cation Channel
• Transient Receptor Potential Channels
• Trpa1 protein, mouse
• Oxaliplatin
• Bortezomib
• Thioctic Acid

Topics

• Acetanilides (pharmacology)
• Animals
• Antineoplastic Agents (toxicity)
• Boronic Acids (toxicity)
• Bortezomib
• Mice
• Mice, Inbred C57BL
• Organoplatinum Compounds (toxicity)
• Oxaliplatin
• Peripheral Nervous System Diseases (chemically induced, prevention & control)
• Purines (pharmacology)
• Pyrazines (toxicity)
• TRPA1 Cation Channel
• Thioctic Acid (pharmacology)
• Transient Receptor Potential Channels (analysis, antagonists & inhibitors, physiology)