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.
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DOI：
10.1016/j.exphem.2013.09.005
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发表时间：
2013-12
影响因子：
2.6
通讯作者：
Russell, Stephen J.
中科院分区：
文献类型：
--
作者：
Yarde, Danielle N.;Nace, Rebecca A.;Russell, Stephen J.
多发性骨髓瘤细胞对水泡性口炎病毒（VSV）的溶瘤作用高度敏感，VSV特异性靶向并杀死癌细胞。骨髓瘤细胞对临床批准的蛋白酶体抑制剂硼替佐米的细胞毒性作用也非常敏感。因此，我们试图确定VSV和硼替佐米的组合是否会增强肿瘤细胞杀伤。然而，如本文所示，在体外组合这两种药剂导致拮抗作用。我们发现硼替佐米抑制VSV复制和传播。我们发现硼替佐米抑制VSV诱导的NF-κB活化，并且使用NF-κ B特异性抑制剂BMS-345541，VSV需要NF-κB活性才能在骨髓瘤细胞中有效扩散。与其他癌细胞系相反，当骨髓瘤细胞用干扰素（IFN）-β预处理时，BMS-345541未恢复病毒滴度。因此，用硼替佐米或BMS-345541抑制NF-κB活性导致体外骨髓瘤细胞中VSV滴度降低。然而，当VSV和硼替佐米在体内组合时，在两种同源的免疫活性骨髓瘤模型中，该组合比VSV作为单一药剂更大程度地降低肿瘤负荷。与VSV单独治疗相比，当小鼠伴随硼替佐米治疗时，肿瘤内VSV病毒载量不变。据我们所知，这是第一份分析VSV和硼替佐米在体内组合的报告。尽管在体外观察到VSV和硼替佐米之间的拮抗作用，但在其宿主环境中分析这些细胞显示硼替佐米增强VSV应答，表明这种组合也将增强骨髓瘤患者的应答。
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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