The Clinically Approved Proteasome Inhibitor PS-341 Efficiently Blocks Influenza A Virus and Vesicular Stomatitis Virus Propagation by Establishing an Antiviral State

Dudek, Sabine Eva; Luig, Christina; Pauli, Eva-Katharina; Schubert, Ulrich S.; Ludwig, Stephan

doi:10.1128/jvi.00533-10

Cited by 45 publications

(38 citation statements)

References 78 publications

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“…Similarly, others have shown antagonism in vitro in other cell types as well. Specifically, Neznanov et al found that bortezomib inhibits VSV protein synthesis via stimulation of stress-related processes in HeLa cells [40], and Dudek et al reported that bortezomib activates NF-κB, resulting in an antiviral state that ultimately inhibits VSV propagation in A549 adenocarcinoma cells [39]. However, unlike the results reported by Dudek, we show that bortezomib does not activate but inhibits NF-κB in myeloma cells (Figure 3).…”

Section: Discussioncontrasting

confidence: 78%

“…We show that bortezomib and VSV are antagonistic in myeloma cell lines and that bortezomib inhibits VSV replication and spread in these cells. Similarly, antagonism between bortezomib and VSV has been reported in vitro in other cell types as well [39, 40]. In vivo , however, using two syngeneic, immunocompetent mouse myeloma models, we found that bortezomib does not affect intra-tumoral VSV titers and that this drug actually enhances tumor reduction when compared to single-agent VSV treatment.…”

Section: Introductionsupporting

confidence: 75%

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Oncolytic vesicular stomatitis virus and bortezomib are antagonistic against myeloma cells in vitro but have additive anti-myeloma activity in vivo

Yarde¹,

Nace²,

Russell³

2013

Experimental Hematology

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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 if 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 in order to efficiently spread in myeloma cells. In contrast to other cancer cell lines, viral titer is not recovered by BMS-345541 when myeloma cells are pre-treated with interferon (IFN)-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 as a single agent. Intra-tumoral VSV viral load is unchanged when mice are concomitantly treated with bortezomib as compared to VSV treatment alone. To our knowledge, this is the first report analyzing 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.

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Section: Discussioncontrasting

confidence: 78%

Section: Introductionsupporting

confidence: 75%

Oncolytic vesicular stomatitis virus and bortezomib are antagonistic against myeloma cells in vitro but have additive anti-myeloma activity in vivo

Yarde¹,

Nace²,

Russell³

2013

Experimental Hematology

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“…This effect is thought to be due to the induction of C/EBPβ, a cellular transcription factor that can then initiate the activation of EBV lytic gene expression (31). While bortezomib has been shown to increase EBV replication, other studies have also found that bortezomib inhibits VSV via activation of NF-κB, resulting in an antiviral state that ultimately inhibits VSV propagation (32). Consistent with these reports, treatment of myeloma cells with bortezomib was was found to inhibit VSV replication and show less than additive cell killing in vitro (33).…”

Section: Discussionmentioning

confidence: 99%

Bortezomib-Induced Unfolded Protein Response Increases Oncolytic HSV-1 Replication Resulting in Synergistic Antitumor Effects

Yoo

Hurwitz

Bolyard

et al. 2014

Clinical Cancer Research

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Background Bortezomib is an FDA-approved proteasome inhibitor, and oncolytic HSV-1 (oHSV) is a promising therapeutic approach for cancer. We tested the impact of combining bortezomib with oHSV for anti-tumor efficacy. Methods The synergistic interaction between oHSV and bortezomib was calculated using Chou-Talalay analysis. Viral replication was evaluated using plaque assay and immune fluorescence. Western-blot assays were used to evaluate induction of ER stress and unfolded protein response (UPR). Inhibitors targeting Hsp90 were utilized to investigate the mechanism of cell killing. Anti-tumor efficacy in vivo was evaluated using subcutaneous and intracranial tumor xenografts of glioma and head and neck cancer. Survival was analyzed by Kaplan-Meier curves and two-sided log rank test. Results Combination treatment with bortezomib and oHSV, 34.5ENVE, displayed strong synergistic interaction in ovarian cancer, head & neck cancer, glioma, and malignant peripheral nerve sheath tumor (MPNST) cells. Bortezomib treatment induced ER stress, evident by strong induction of Grp78, CHOP, PERK and IRE1α (western blot analysis) and the UPR (induction of hsp40, 70 and 90). Bortezomib treatment of cells at both sublethal and lethal doses increased viral replication (p value <0.001), but inhibition of Hsp90 ablated this response, reducing viral replication and synergistic cell killing. The combination of bortezomib and 34.5ENVE significantly enhanced anti-tumor efficacy in multiple different tumor models in vivo. Conclusions The dramatic synergy of bortezomib and 34.5ENVE is mediated by bortezomib- induced UPR and warrants future clinical testing in patients.

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“…On the other hand, the proteasome inhibitor drug bortezomib, or PS-341, which activates the NF-jB pathway through degradation of IjB, also inhibits IAV replication. Bortezomib is a clinically approved anticancer drug and has been demonstrated to exert antiviral activity by upregulating the expression of antiviral genes such as interleukin 6 and MxA [184]. Therefore, both inhibitors and activators of the NFjB pathway can serve as potential antivirals.…”

Section: Host Cellular Factors As Anti-influenza Targetsmentioning

confidence: 99%

Interplay between influenza A virus and host factors: targets for antiviral intervention

2015

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Influenza A viruses (IAVs) pose a major public health threat worldwide. Recent experience with the 2013 H7N9 outbreak in China and the 2009 "swine flu" pandemic have shown that antiviral vaccines and drugs fall short of controlling the spread of disease in a timely and effective manner. Major problems include rapid emergence of drug-resistant influenza virus strains and the slow process of vaccine production. With the threat of a highly pathogenic H5N1 bird-flu pandemic looming large, it is crucial to develop novel ways of combating influenza A viruses. Targeting the host factors critical for influenza A virus replication has shown promise as a strategy to develop novel antiviral molecules with broad-spectrum protection. In this review, we summarize the role of currently identified host factors that play a critical role in the influenza A virus life cycle and discuss the most promising candidates for anti-influenza therapeutics.

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The Clinically Approved Proteasome Inhibitor PS-341 Efficiently Blocks Influenza A Virus and Vesicular Stomatitis Virus Propagation by Establishing an Antiviral State

Cited by 45 publications

References 78 publications

Oncolytic vesicular stomatitis virus and bortezomib are antagonistic against myeloma cells in vitro but have additive anti-myeloma activity in vivo

Oncolytic vesicular stomatitis virus and bortezomib are antagonistic against myeloma cells in vitro but have additive anti-myeloma activity in vivo

Bortezomib-Induced Unfolded Protein Response Increases Oncolytic HSV-1 Replication Resulting in Synergistic Antitumor Effects

Interplay between influenza A virus and host factors: targets for antiviral intervention

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