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

Watanabe T, Nagase K, Chosa M, Tobinai K - Br. J. Cancer (2010)

Bottom Line: A tractable system to evaluate combination drugs for use with bortezomib is essential to enable continuing clinical benefit from this drug.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.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).

View Article: PubMed Central - PubMed

Affiliation: Hematology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. takawata@ncc.go.jp

ABSTRACT

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.

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Related in: MedlinePlus

Combination treatments with bortezomib can augment the exocytosis of misfolded proteins through the chaperone-mediated autophagy of Schwann cells. The distributions of HSP70/HSC70 (red), a chaperone protein, and LAMP-2A (green), a lysosomal membrane protein with a specific role in chaperone-mediated autophagy, are shown in response to combination treatments with (A) SAHA, (B) 17-AAG, and (C) CZP. The colocalisation of both proteins is evidenced by the small rounded structures outside of the cells that appear as an orange signal (arrowheads). Bar, 20 μ.
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fig4: Combination treatments with bortezomib can augment the exocytosis of misfolded proteins through the chaperone-mediated autophagy of Schwann cells. The distributions of HSP70/HSC70 (red), a chaperone protein, and LAMP-2A (green), a lysosomal membrane protein with a specific role in chaperone-mediated autophagy, are shown in response to combination treatments with (A) SAHA, (B) 17-AAG, and (C) CZP. The colocalisation of both proteins is evidenced by the small rounded structures outside of the cells that appear as an orange signal (arrowheads). Bar, 20 μ.

Mentions: To analyse the molecular mechanisms underlying the enhanced exocytosis of misfolded proteins in Schwann cells, we used an antibodies against the HSP70 chaperone protein and the receptor for chaperone-mediated autophagy (CMA) at the lysosomal membrane (which is a unique isoform of LAMP-2, LAMP-2A) (Cuervo and Dice, 2000; Kaushik et al, 2006). After treatment with SAHA, 17-AAG, or CZP (Figure 4A, B, or C, respectively) followed by bortezomib, HSP70 and LAMP-2A were found to colocalise in structures outside of the cells.


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

Watanabe T, Nagase K, Chosa M, Tobinai K - Br. J. Cancer (2010)

Combination treatments with bortezomib can augment the exocytosis of misfolded proteins through the chaperone-mediated autophagy of Schwann cells. The distributions of HSP70/HSC70 (red), a chaperone protein, and LAMP-2A (green), a lysosomal membrane protein with a specific role in chaperone-mediated autophagy, are shown in response to combination treatments with (A) SAHA, (B) 17-AAG, and (C) CZP. The colocalisation of both proteins is evidenced by the small rounded structures outside of the cells that appear as an orange signal (arrowheads). Bar, 20 μ.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2990589&req=5

fig4: Combination treatments with bortezomib can augment the exocytosis of misfolded proteins through the chaperone-mediated autophagy of Schwann cells. The distributions of HSP70/HSC70 (red), a chaperone protein, and LAMP-2A (green), a lysosomal membrane protein with a specific role in chaperone-mediated autophagy, are shown in response to combination treatments with (A) SAHA, (B) 17-AAG, and (C) CZP. The colocalisation of both proteins is evidenced by the small rounded structures outside of the cells that appear as an orange signal (arrowheads). Bar, 20 μ.
Mentions: To analyse the molecular mechanisms underlying the enhanced exocytosis of misfolded proteins in Schwann cells, we used an antibodies against the HSP70 chaperone protein and the receptor for chaperone-mediated autophagy (CMA) at the lysosomal membrane (which is a unique isoform of LAMP-2, LAMP-2A) (Cuervo and Dice, 2000; Kaushik et al, 2006). After treatment with SAHA, 17-AAG, or CZP (Figure 4A, B, or C, respectively) followed by bortezomib, HSP70 and LAMP-2A were found to colocalise in structures outside of the cells.

Bottom Line: A tractable system to evaluate combination drugs for use with bortezomib is essential to enable continuing clinical benefit from this drug.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.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).

View Article: PubMed Central - PubMed

Affiliation: Hematology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. takawata@ncc.go.jp

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus