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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.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).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.

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.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).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.

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