Calpain inhibition protects against Taxol-induced sensory neuropathy

Abstract

Taxol is a highly effective anticancer agent that causes peripheral neuropathy as its major toxic side effect. The neuropathy is characterized by degeneration of sensory axons that may be severe enough to be dose limiting. Axonal degeneration involves the activation of the calcium-activated proteases calpains, and here we tested whether systemic inhibition of calpains with the peptide α-ketoamide calpain inhibitor AK295 can reduce the clinical and pathological effects of Taxol in a rodent model of Taxol neuropathy. In mice with Taxol neuropathy, AK295 reduced the degree of axonal degeneration in sensory nerve roots, and improved clinical measures of neuropathy, including behavioural and electrophysiological function. These findings were consistent for both 3- and 6-week models of neuropathy. In vitro, Taxol caused activation of both calpains and caspases in PC12 cells. AK295 inhibited the activation of calpains but did not interfere with the antimitotic effects of Taxol on microtubules, nor did it inhibit caspase-mediated cell death. These data implicate calpains in the pathogenesis of Taxol neuropathy, and demonstrate that AK295 can prevent axonal degeneration and clinical neuropathy in mice. In addition, AK295 did not interfere with the primary antineoplastic effects of Taxol on microtubules and cell death, suggesting that systemic calpain inhibition may be a good strategy for preventing neuropathy in patients being treated with Taxol.