Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, U.S.A.
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, U.S.A.
In Vivo. 2021 Jan-Feb;35(1):141-145. doi: 10.21873/invivo.12241.
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 significantly enhances endoplasmic reticulum (ER) stress and induces selective cell death in multiple cell line models (in vitro).
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.
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.
Our findings suggest that the induction of proteotoxicity provides a promising new target for developing anticancer drugs.
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，目前正在被重新定位为一种抗癌药物。氯喹是一种溶酶体靶向抗疟药物，可抑制自噬。据报道，奈非那韦和氯喹联合使用可显著增强内质网（ER）应激，并在多种细胞系模型（体外）中诱导选择性细胞死亡。
我们使用细胞增殖测定法评估了这些药物在体外对人非小细胞肺癌细胞系的影响，并在体内使用细胞系衍生的异种移植小鼠模型进行了临床前治疗研究。
在体外，这种联合用药增强了对非小细胞肺癌细胞增殖的抑制作用，同时增加了蛋白毒性，包括内质网应激和细胞凋亡。在体内，人非小细胞肺癌异种移植肿瘤的生长受到抑制，这与体外的细胞凋亡和 ER 应激诱导以及非小细胞肺癌的生长相关。
我们的研究结果表明，诱导蛋白毒性为开发抗癌药物提供了一个有前途的新靶点。
