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.
Hematology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. takawata@ncc.go.jp
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Watanabe
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Nagase
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Chosa
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Tobinai
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D016227:Benzoquinones / Q000494:pharmacology*; D001897:Boronic Acids / Q000627:therapeutic use; D000069286:Bortezomib; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002998:Clonazepam / Q000494:pharmacology*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D009101:Multiple Myeloma / Q000188:drug therapy / Q000473:pathology; D009442:Neurilemmoma; D017510:Protein Folding; D057165:Proteostasis Deficiencies / Q000473:pathology; D011719:Pyrazines / Q000627:therapeutic use; D051381:Rats; D012583:Schwann Cells / Q000166:cytology / Q000473:pathology
D000970:Antineoplastic Agents; D016227:Benzoquinones; D001897:Boronic Acids; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D011719:Pyrazines; C112765:tanespimycin; D002998:Clonazepam; D000069286:Bortezomib