Abstract
Heat shock protein 90 (Hsp90) is a promising target for anti-tumor therapy. We previously reported the anti-tumor activity of a novel Hsp90 inhibitor, KW-2478, in multiple myeloma (MM) as a single agent. In this study, we examined the combinational effect of KW-2478 and bortezomib, a proteasome inhibitor, in vitro and in vivo. In vitro, KW-2478 enhanced bortezomib-induced cell growth inhibition, both in MM cell lines and primary patient MM cells. The combination of KW-2478 and bortezomib also induced caspase activation in MM cell lines. Interestingly, the combination synergistically enhanced the expression of Hsp70B, a homolog of Hsp70, in human MM cells and peripheral blood mononuclear cells, indicating Hsp70B could be a surrogate biomarker for the combination of Hsp90 and proteasome inhibitors. In vivo, the combination of KW-2478 with bortezomib showed synergistic anti-tumor activity without significant body weight loss in a subcutaneously inoculated human myeloma model. Furthermore, the combination also showed synergistic reduction of tumor burden in bone marrow in an orthotopic myeloma model. Our results strongly suggest that combination of KW-2478 with bortezomib could exhibit enhanced anti-tumor activity against human myeloma.
Highlights
Multiple myeloma (MM) is a plasma-cell malignancy characterized by accumulation of malignant cells in the bone marrow and production of a monoclonal immunoglobulin (M protein)
As MM cells constantly produce a large amount of M protein, they are susceptible to ER stress; inhibition of the proteasome results in accumulation of immunoglobulin-derived defective ribosomal products, namely misfolded/unfolded proteins (UPR), and this accumulation causes apoptosis following extensive ER stress.[6]
Apoptosis induced by bortezomib combined with KW-2478 in MM cell lines
Summary
Multiple myeloma (MM) is a plasma-cell malignancy characterized by accumulation of malignant cells in the bone marrow and production of a monoclonal immunoglobulin (M protein). Treatment strategies for MM have changed substantially over the past 10 years following the introduction of bortezomib and the immunomodulatory drugs, thalidomide and lenalidomide. These drugs have improved patient survival, the disease is still incurable in the majority of patients. As MM cells constantly produce a large amount of M protein, they are susceptible to ER stress; inhibition of the proteasome results in accumulation of immunoglobulin-derived defective ribosomal products, namely misfolded/unfolded proteins (UPR), and this accumulation causes apoptosis following extensive ER stress.[6] The activity of bortezomib may be enhanced by combination with drugs that induce misfolded/UPR accumulation
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