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

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Heat shock protein 70 (HSP70) pathways protect tumor cells from proteotoxic stress.
• HSP70 is a potential therapeutic target for multiple myeloma.
• Proteasome inhibitors like bortezomib are established treatments for multiple myeloma.

Purpose of the Study:

• To investigate the efficacy of HSP70 inhibitor VER155008, proteasome inhibitor bortezomib, and their combination in multiple myeloma treatment.
• To evaluate tumor growth reduction and inhibition in vitro and in vivo models.

Main Methods:

• Bioluminescent multiple myeloma cell lines (RPMI8226-LUC-PURO, U266-LUC-PURO) were treated with VER155008 and/or bortezomib.
• Subcutaneous xenograft models in immunodeficient mice were established to assess tumor growth.
• Bioluminescence imaging was utilized to monitor tumor response and growth inhibition.

Main Results:

• Bortezomib induced significant late apoptosis (~60%) in RPMI8226-LUC-PURO cells.
• VER155008, alone or with bortezomib, induced significant cell death (~60%) in U266-LUC-PURO cells.
• Both single agents and the combination treatment reduced tumor growth in vivo across both cell lines, with notable efficacy in U266-LUC-PURO cells (bearing 17p deletion).

Conclusions:

• The combination of proteasome and HSP70 inhibitors demonstrates synergistic potential in inducing cancer cell death.
• This combination therapy shows efficacy in inhibiting multiple myeloma tumor growth both in vitro and in vivo.
• The U266-LUC-PURO cell line, particularly with 17p deletion, showed a pronounced benefit from the combined treatment strategy.