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

刘立柱; 李超艺; 林诗炜; 曲野; 汤强

doi:10.16098/j.issn.0529-1356.2022.04.013

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解剖学报 ›› 2022, Vol. 53 ›› Issue (4) : 498-506. DOI: 10.16098/j.issn.0529-1356.2022.04.013

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

刘立柱¹ 李超艺^1* 林诗炜¹ 曲野¹ 汤强²

作者信息 +

PI3K inhibitor ZSTK474 enhancing the antitumor of vesicular stomatitis virus Δ51 against osteosarcoma

LIU Li-zhu¹ LI Chao-yi^1* LIN Shi-wei¹ QU Ye¹ TANG Qiang ²#br#

Author information +

文章历史 +

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。

Abstract

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 virus Δ51 (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.

导出引用

刘立柱李超艺林诗炜曲野汤强. 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[J]. 解剖学报. 2022, 53(4): 498-506 https://doi.org/10.16098/j.issn.0529-1356.2022.04.013

LIU Li-zhu LI Chao-yi LIN Shi-wei QU Ye TANG Qiang. PI3K inhibitor ZSTK474 enhancing the antitumor of vesicular stomatitis virus Δ51 against osteosarcoma[J]. Acta Anatomica Sinica. 2022, 53(4): 498-506 https://doi.org/10.16098/j.issn.0529-1356.2022.04.013

中图分类号： R730.5

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