Combining Nelfinavir With Chloroquine Inhibits In Vivo Growth of Human Lung Cancer Xenograft Tumors
Combining Nelfinavir With Chloroquine Inhibits In Vivo Growth of Human Lung Cancer Xenograft Tumors
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DOI：
10.21873/invivo.12241
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发表时间：
2021-01-01
期刊：
影响因子：
2.3
通讯作者：
Dennis, Phillip A.
中科院分区：
文献类型：
--
作者：
Lopiccolo, Jaclyn;Kawabata, Shigeru;Dennis, Phillip A.
背景/目的：奈非那韦是一种人类免疫缺陷病毒蛋白酶抑制剂，目前正被重新定位为抗癌药物。氯喹是一种抗疟疾溶酶体药物，可抑制自噬。据报道，奈非那韦和氯喹的组合在多种细胞系模型（体外）中显着增强内质网（ER）应激并诱导选择性细胞死亡。材料和方法：我们使用细胞增殖测定评估了这些药物组合对体外人类 NSCLC 细胞系的影响，并使用体内细胞系衍生的异种移植小鼠模型进行了临床前治疗研究。结果：在体外，这种组合增强了对 NSCLC 细胞增殖的抑制作用，并增加了蛋白毒性，包括 ER 应激和细胞凋亡。在体内，人 NSCLC 异种移植肿瘤的生长受到抑制，这与细胞凋亡增加和 ER 应激诱导以及体外 NSCLC 生长相关。结论：我们的研究结果表明，蛋白毒性的诱导为开发抗癌药物提供了一个有前景的新靶点。
Background/Aim: Nelfinavir is a human immunodeficiency virus protease inhibitor that is currently being repositioned as an anticancer drug. Chloroquine, an anti-malarial lysosomotropic drug, inhibits autophagy. It has been reported that the combination of nelfinavir and chloroquine signcantly enhances endoplasmic reticulum (ER) stress and induces selective cell death in multiple cell line models (in vitro). Materials and Methods: We assessed the effects of the combination of these drugs on human NSCLC cell lines in vitro using cell proliferation assay and performed preclinical treatment studies using cell line-derived xenograft mouse models in vivo. Results: In vitro, this combination enhanced inhibition of NSCLC cell proliferation with increased proteotoxicity, including ER stress, and apoptosis. In vivo, the growth of human NSCLC xenograft tumors was inhibited, which correlated with increased apoptosis and induction of ER stress as well as NSCLC growth in vitro. Conclusion: Our findings suggest that the induction of proteotoxicity provides a promising new target for developing anticancer drugs.