Schwann cell autophagy induced by SAHA, 17-AAG, or clonazepam can reduce bortezomib-induced peripheral neuropathy

BACKGROUND: The proteasome inhibitor bortezomib has improved the survival of patients with multiple myeloma but bortezomib-induced peripheral neuropathy (BiPN) has emerged as a serious potential complication of this therapy. Animal studies suggest that bortezomib predominantly causes pathological changes in Schwann cells. A tractable system to evaluate combination drugs for use with bortezomib is essential to enable continuing clinical benefit from this drug. METHODS: Rat schwannoma cells were pretreated with vincristine (VCR), histone deacetylase inhibitors, anticonvulsants, or a heat-shock protein 90 (HSP90) inhibitor. To then monitor aggresome formation as a result of proteasome inhibition and the activation of chaperone-mediated autophagy (CMA), we performed double-labelling immunofluorescent analyses of a cellular aggregation-prone protein marker. RESULTS: Aggresome formation was interrupted by VCR, whereas combination treatments with bortezomib involving suberoylanilide hydroxamic acid, 17-allylamino-17-demethoxy-geldanamycin, or clonazepam appear to facilitate the disposal of unfolded proteins via CMA, inducing HSP70 and lysosome-associated membrane protein type 2A (LAMP-2A). CONCLUSIONS: This schwannoma model can be used to test BiPN-reducing drugs. The present data suggest that aggresome formation in Schwann cells is a possible mechanism of BiPN, and drugs that induce HSP70 or LAMP-2A have the potential to alleviate this complication. Combination clinical trials are warranted to confirm the relevance of these observations.