Proteasome and heat shock protein 70 (HSP70) inhibitors as therapeutic alternative in multiple myeloma
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Angela Isabel Pereira Eugênio1, Veruska Lia Fook-Alves1, Mariana Bleker de Oliveira1, Rodrigo Carlini Fernando1, Daniela B. Zanatta2, Bryan Eric Strauss2, Maria Regina Regis Silva3, Marimélia Aparecida Porcionatto4 and Gisele Wally Braga Colleoni1
1Discipline of Hematology e Hemotherapy, Department of Clinical and Experimental Oncology, Universidade Federal de São Paulo, UNIFESP, São Paulo, SP, Brazil
2Center of Translational Investigation in Oncology, Cancer Institute of the State of São Paulo, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
3Department of Pathology, Universidade Federal de São Paulo, UNIFESP, São Paulo, SP, Brazil
4Department of Biochemistry, Universidade Federal de São Paulo, UNIFESP, São Paulo, SP, Brazil
Gisele Wally Braga Colleoni, email: [email protected]
Keywords: multiple myeloma; HSP70; ubiquitin-proteasome system; unfolded protein response; autophagy
Received: May 04, 2017 Accepted: November 05, 2017 Published: December 01, 2017
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 ~60% of late apoptosis in RPMI8226-LUC-PURO (without additional benefit of VER155008 in this cell line). However, U266-LUC-PURO showed ~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.
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