Doxorubicin Synergizes Bortezomib-Induced Multiple Myeloma Cell Death By Inhibiting Aggresome Formation Leading to ER Stress and Apoptosis

Bortezomib is a proteasome inhibitor that eradicates multiple myeloma (MM) cells by accumulating toxic misfolded proteins. However, the emergence of bortezomib resistance remains a significant challenge in MM treatment. An aggresome is a subcellular structure enclosed by vimentin that forms when cells are treated with proteasome inhibitors. Aggresomes sequester misfolded proteins bound and transported by HDAC6 and dynein before they are degraded by autophagy, thereby potentially increasing the efficacy of bortezomib in MM treatment. To this end, we screened anticancer drugs for their potential to block aggresome formation and synergize bortezomib-induced MM cell death. The results showed that doxorubicin synergized bortezomib-mediated cytotoxicity and impaired bortezomib-induced aggresome formation in U266B1 cells. Mechanistic studies revealed that doxorubicin downregulated aggresome-promoting factors such as vimentin, HDAC6, and dynein, while enhancing pro-apoptotic pathways by inducing ER stress in bortezomib-treated U266B1 cells. Remarkably, doxorubicin did not potentiate cell death triggered by proteasome inhibitors that do not stimulate aggresome formation, and the combined treatment of bortezomib and doxorubicin failed to generate synergistic cell death in multiple myeloma cell lines lacking aggresome formation activity. These data demonstrate that doxorubicin synergizes bortezomib-induced cell death by blocking aggresome formation. Our studies suggest the therapeutic potential of combining bortezomib and doxorubicin in the treatment of MM.

No relevant conflicts of interest to declare.