Multiple myeloma cells are highly sensitive to the oncolytic effects of
vesicular stomatitis virus (VSV), which specifically targets and kills
cancer cells. Myeloma cells are also exquisitely sensitive to the cytotoxic effects of the clinically approved
proteasome inhibitor bortezomib. Therefore, we sought to determine whether the combination of VSV and
bortezomib would enhance
tumor cell killing. However, as shown here, combining these two agents in vitro results in antagonism. We show that
bortezomib inhibits VSV replication and spread. We found that
bortezomib inhibits VSV-induced NF-κB activation and, using the NF-κB-specific inhibitor
BMS-345541, that VSV requires NF-κB activity to spread efficiently in myeloma cells. In contrast to other
cancer cell lines, viral titer is not recovered by
BMS-345541 when myeloma cells are pretreated with
interferon β. Thus, inhibiting NF-κB activity, either with
bortezomib or
BMS-345541, results in reduced VSV titers in myeloma cells in vitro. However, when VSV and
bortezomib are combined in vivo in two syngeneic, immunocompetent myeloma models, the combination reduces
tumor burden to a greater degree than VSV does as a single agent. Intratumoral VSV viral load is unchanged when mice are treated concomitantly with
bortezomib compared to VSV treatment alone. To our knowledge, this report is the first to analyze the combination of VSV and
bortezomib in vivo. Although antagonism between VSV and
bortezomib is seen in vitro, analyzing these cells in the context of their host environment shows that
bortezomib enhances VSV response, suggesting that this combination will also enhance response in myeloma patients.