*2.4. Proteasome Inhibitors*

Another approach to indirectly inhibit NF-κB is by blocking proteasomal degradation. The rationale is that proteasome inhibition blocks NF-kBs release from the IKKβ complex (Figure 2). Indeed, the proteasome inhibitor bortezomib improved the viral replication of oncolytic HSV and also enhanced necroptotic tumor cell death through increased endoplasmatic reticulum (ER) stress and unfolded protein response (UPR) (Figure 4C) [98–100].

However, when bortezomib was combined with VSV, a reduction in replication and spread was seen in myeloma cells despite NF-κB activation being blocked. Interestingly, despite these antagonistic effects in vitro, co-treatment in vivo did improve the antitumor efficacy [101]. Similarly, another proteasome inhibitor PS-341 blocked the replication of VSV in human adenocarcinoma A549 cells [102] and infection with HSV strains. These seemingly contradictory studies make the combination of proteasome inhibitors and OVs a treatment option that needs to be further elucidated.
