Combination Therapy with Reovirus and ATM Inhibitor Enhances Cell Death and Virus Replication in Canine Melanoma
Combination Therapy with Reovirus and ATM Inhibitor Enhances Cell Death and Virus Replication in Canine Melanoma
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DOI：
10.1016/j.omto.2019.08.003
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发表时间：
2019-12-20
影响因子：
5.7
通讯作者：
Mizuno, Takuya
中科院分区：
文献类型：
--
作者：
Igase, Masaya;Shibutani, Shusaku;Mizuno, Takuya
呼肠孤病毒溶瘤病毒治疗是一种很有前途的新型抗癌治疗方法，有可能用于人类和狗。由于呼肠孤病毒单一疗法对人类和犬类癌症患者的疗效有限，因此有必要开发一种联合疗法。为了确定这种组合的候选成分，我们筛选了285种化合物药物库，以增强犬黑色素瘤细胞系中呼肠孤病毒的细胞毒性。在这里，我们表明暴露于共济失调毛细血管扩张突变蛋白（ATM）抑制剂增强呼肠孤病毒的溶瘤潜能在六个测试犬黑色素瘤细胞系中的五个。具体来说，ATM抑制剂在促进溶酶体活性的同时增强了呼肠孤病毒在癌细胞中的复制，与单独使用呼肠孤病毒相比，增加了caspase依赖性凋亡的比例和G2/M的细胞周期停滞。总的来说，我们的研究表明呼肠孤病毒和ATM抑制剂的联合治疗可能是一种有吸引力的癌症治疗选择。
Oncolytic virotherapy using reovirus is a promising new anti-cancer treatment with potential for use in humans and dogs. Because reovirus monotherapy shows limited efficacy in human and canine cancer patients, the clinical development of a combination therapy is necessary. To identify candidate components of such a combination, we screened a 285-compound drug library for those that enhanced reovirus cytotoxicity in a canine melanoma cell line. Here, we show that exposure to an inhibitor of the ataxia telangiectasia mutated protein (ATM) enhances the oncolytic potential of reovirus in five of six tested canine melanoma cell lines. Specifically, the ATM inhibitor potentiated reovirus replication in cancer cells along with promoting the lysosomal activity, resulting in an increased proportion of caspase-dependent apoptosis and cell cycle arrest at G2/M compared to those observed with reovirus alone. Overall, our study suggests that the combination of reovirus and the ATM inhibitor may be an attractive option in cancer therapy.