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

Author(s)

Pereira Eugenio, Angela Isabel ^[1] ; Fook-Alves, Veruska Lia ^[1] ; de Oliveira, Mariana Bleker ^[1] ; Fernando, Rodrigo Carlini ^[1] ; Zanatta, Daniela B. ^[2] ; Strauss, Bryan Eric ^[2] ; Regis Silva, Maria Regina ^[3] ; Porcionatto, Marimelia Aparecida ^[4] ; Braga Colleoni, Gisele Wally ^[1]

Affiliation

^[1] Univ Fed Sao Paulo, UNIFESP, Dept Clin & Expt Oncol, Discipline Hematol & Hemotherapy, Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Fac Med, Canc Inst State Sao Paulo, Ctr Translat Invest Oncol, Sao Paulo, SP - Brazil

^[3] Univ Fed Sao Paulo, UNIFESP, Dept Pathol, Sao Paulo, SP - Brazil

^[4] Univ Fed Sao Paulo, UNIFESP, Dept Biochem, Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: ONCOTARGET; v. 8, n. 70, p. 114698-114709, DEC 29 2017.
• Web of Science Citations: 4

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. (AU)

• FAPESP's process: 10/17668-6 - Identification of biomarkers and possible therapeutical targets in B-cell lymphoproliferative disorders
• Grantee: Gisele Wally Braga Colleoni
• Support Opportunities: Research Projects - Thematic Grants