Proteasome and heat shock protein 70 (HSP70) inhibitors as therapeutic alternative in multiple myeloma

Proteasome and heat shock protein 70 (HSP70) inhibitors as therapeutic alternative in multiple myeloma

Author Pereira Eugenio, Angela Isabel Autor UNIFESP Google Scholar
Fook-Alves, Veruska Lia Autor UNIFESP Google Scholar
de Oliveira, Mariana Bleker Autor UNIFESP Google Scholar
Fernando, Rodrigo Carlini Autor UNIFESP Google Scholar
Zanatta, Daniela B. Google Scholar
Strauss, Bryan Eric Google Scholar
Regis Silva, Maria Regina Autor UNIFESP Google Scholar
Porcionatto, Marimelia Aparecida Autor UNIFESP Google Scholar
Braga Colleoni, Gisele Wally Autor UNIFESP Google Scholar
Abstract HSP70 connects multiple signaling pathways that work synergistically to protect tumor cells from death by proteotoxic stress and represents a possible target to establish a new approach for multiple myeloma treatment. Therefore, bioluminescent cell lines RPMI8226-LUC-PURO and U266-LUC-PURO were treated with HSP70 (VER155008) and/or proteasome (bortezomib) inhibitors and immunodeficient mice were used for subcutaneous xenograft models to evaluate tumor growth reduction and tumor growth inhibition after treatment. Bioluminescence imaging was used to follow tumor response. Treatment with bortezomib showed similar to 60% of late apoptosis in RPMI8226-LUC-PURO (without additional benefit of VER155008 in this cell line). However, U266-LUC-PURO showed similar to 60% of cell death after treatment with VER155008 (alone or with bortezomib). RPMI8226-LUC-PURO xenograft presented tumor reduction by bioluminescence imaging after treatment with bortezomib, VER155008 or drug combination compared to controls. Treatment with bortezomib, alone or combined with VER155008, showed inhibition of tumor growth assessed by bioluminescence imaging after one week in both RPMI8226-LUC-PURO and U266-LUC-PURO cell lines when compared to controls. In conclusion, our study shows that the combination of proteasome and HSP70 inhibitors induced cell death in tumor cells in vitro (late apoptosis induction) and in vivo (inhibition of tumor growth) with special benefit in U266-LUC-PURO, bearing 17p deletion.
Keywords multiple myeloma
ubiquitin-proteasome system
unfolded protein response
xmlui.dri2xhtml.METS-1.0.item-coverage Orchard Park
Language English
Sponsor Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Brazil
Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP), Brazil [2010/17668-6]
Grant number FAPESP [2010/17668-6]
Date 2017
Published in Oncotarget. Orchard Park, v. 8, n. 70, p. 114698-114709, 2017.
ISSN 1949-2553 (Sherpa/Romeo, impact factor)
Publisher Impact Journals Llc
Extent 114698-114709
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000419571000030

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