PI3K抑制剂ZSTK474增强水泡性口炎病毒Δ51在骨肉瘤中的抗肿瘤作用  

PI3K inhibitor ZSTK474 enhancing the antitumor of vesicular stomatitis virusΔ51 against osteosarcoma

作　　者：刘立柱 李超艺 林诗炜 曲野 汤强 LIU Li-zhu;LI Chao-yi;LIN Shi-wei;QU Ye;TANG Qiang(Department of Trauma Surgery,the Second Affiliated Hospital of Hainan Medical College,Haikou 570311,China;Hainan Key Laboratory of Oncology and Intervention,Hainan Medical College,Haikou 571199,China)

机构地区：[1]海南医学院第二附属医院创伤外科,海口570311 [2]海南医学院海南省肿瘤发生与干预重点实验室,海口571199

出　　处：《解剖学报》2022年第4期498-506,共9页Acta Anatomica Sinica

基　　金：海南省卫生健康行业科研项目(19A200063);吴阶平医学基金会临床科研专项基金(320.6750.19079-08)。

摘　　要：目的探讨PI3K抑制剂联合溶瘤病毒是否对骨肉瘤具有溶瘤作用。方法通过MTT法检测细胞活性,寻找可以增强水泡性口炎病毒Δ51(VSVΔ51)抗肿瘤活性的抑制剂;通过电子显微镜观察内质网肿胀以及Western blotting检测凋亡相关蛋白的表达情况,探讨其增强溶瘤活性的机制;通过裸鼠移植瘤模型抑瘤实验验证PI3K抑制剂ZSTK474联合溶瘤病毒VSVΔ51疗法的肿瘤清除能力,并通过免疫组织化学实验验证肿瘤细胞凋亡情况。结果PI3K抑制剂可以作为溶瘤病毒VSVΔ51的增效剂,其通过加强肿瘤细胞内质网应激促进骨肉瘤细胞凋亡(P<0.01)。体内实验也表明,PI3K抑制剂联合溶瘤病毒VSVΔ51可以显著增加对骨肉瘤的溶瘤效果(P<0.001),而且这种联合疗法增强了肿瘤中免疫细胞的浸润(P<0.001)。结论PI3K抑制剂联合溶瘤病毒是一种潜在的骨肉瘤治疗方法。Objective To explore whether PI3K inhibitor combined with oncolytic virus can play an effective oncolytic effect on osteosarcoma.Methods The cytotoxicity to tumor cells was detected by MTT method,and the mechanism of enhancing the anti-tumor activity was explored by observation of the swelling of endoplasmic reticulum using electron microscope and the expression of apoptosis-related proteins using Western blotting.The tumor clearance ability of the combination of the PI3k inhibitor ZSTK474 and vesicular stomatitis virusΔ51(VSVΔ51)was verified by anti-tumor experiment in vivo.The apoptosis of tumor cells was verified by immunohistochemistry.Results PI3K inhibitor could be used as sensitizers of oncolytic VSVΔ51,and confirmed that they promoted the strong apoptosis of osteosarcoma cells by aggravating the stress of endoplasmic reticulum in tumor cells(P<0.01).In vivo experiments also showed that PI3K inhibitors combined with VSVΔ51 could significantly promote the oncolytic effect of osteosarcoma(P<0.001),and this combination therapy enhanced the infiltration of immune cells in the tumor(P<0.001).Conclusion PI3K inhibitors combined with oncolytic virus is a potential therapy for osteosarcoma.

关 键 词：骨肉瘤 溶瘤病毒 水泡性口炎病毒Δ51 磷脂酰肌醇-3激酶抑制剂 免疫印迹法 小鼠 

分 类 号：R730.5[医药卫生—肿瘤]