Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA.
Viruses. 2019 May 10;11(5):431. doi: 10.3390/v11050431.
Previous results have shown that infection with the cytoplasmic-replicating parainfluenza virus 5 mutant P/V-CPI- sensitizes cells to DNA damaging agents, resulting in the enhanced killing of airway cancer cells. Here, we have tested the hypothesis that histone deacetylase (HDAC) inhibitors can also act with P/V-CPI- infection to enhance cancer cell killing. Using human small cell lung cancer and laryngeal cancer cell lines, 10 HDAC inhibitors were tested for their effect on viability of P/V-CPI- infected cells. HDAC inhibitors such as scriptaid enhanced caspase-3/7, -8 and -9 activity induced by P/V-CPI- and overall cell toxicity. Scriptaid-mediated enhanced killing was eliminated in lung cancer cells that were engineered to express a protein which sequesters double stranded RNA. Scriptaid also enhanced cancer cell killing by two other negative strand RNA viruses - the La Crosse virus and vesicular stomatitis virus. Scriptaid treatment enhanced the spread of the P/V-CPI- virus through a population of cancer cells, and suppressed interferon-beta induction through blocking phosphorylation and nuclear translocation of Interferon Regulatory Factor 3 (IRF-3). Taken together, these data support a role for combinations of a cytoplasmic-replicating RNA virus such as the P/V-CPI- mutant along with chemotherapeutic agents.
先前的研究结果表明，细胞质复制副粘病毒 5 突变株 P/V-CPI-感染可使细胞对 DNA 损伤剂敏感，从而增强对气道癌细胞的杀伤作用。在这里，我们检验了一个假设，即组蛋白去乙酰化酶（HDAC）抑制剂也可以与 P/V-CPI-感染协同作用，增强癌细胞杀伤作用。我们使用人小细胞肺癌和喉癌细胞系，测试了 10 种 HDAC 抑制剂对 P/V-CPI-感染细胞活力的影响。组蛋白去乙酰化酶抑制剂，如 scriptaid，可增强 P/V-CPI-诱导的 caspase-3/7、-8 和 -9 活性以及细胞毒性。scriptaid 介导的杀伤增强作用在表达一种可隔离双链 RNA 的蛋白的肺癌细胞中被消除。scriptaid 还通过阻断干扰素调节因子 3（IRF-3）的磷酸化和核易位来增强两种其他负链 RNA 病毒——拉科罗病毒和水疱性口炎病毒对癌细胞的杀伤作用。scriptaid 处理增强了 P/V-CPI-病毒在癌细胞群中的传播，并通过阻断干扰素调节因子 3（IRF-3）的磷酸化和核易位来抑制干扰素-β的诱导。总之，这些数据支持了细胞质复制 RNA 病毒（如 P/V-CPI-突变株）与化学治疗剂联合使用的作用。
