Lu Junwan, Li Yujie, Gong Shiwei, Wang Jiaxin, Lu Xiaoang, Jin Qiumei, Lu Bin, Chen Qin
Protein Quality Control and Diseases Laboratory, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
School of Medicine, Jinhua Polytechnic, Jinhua, 321007, China.
Cell Commun Signal. 2022 Mar 24;20(1):37. doi: 10.1186/s12964-022-00847-x.
Lung cancer remains a major cause of cancer-related mortality throughout the world at present. Repositioning of existing drugs for other diseases is a promising strategy for cancer therapies, which may rapidly advance potentially promising agents into clinical trials and cut down the cost of drug development. Ciclopirox (CPX), an iron chelator commonly used to treat fungal infections, which has recently been shown to have antitumor activity against a variety of cancers including both solid tumors and hematological malignancies in vitro and in vivo. However, the effect of CPX on non-small cell lung cancer (NSCLC) and the underlying mechanism is still unclear.
CCK-8, clonal formation test and cell cycle detection were used to observe the effect of inhibitor on the proliferation ability of NSCLC cells. The effects of CPX on the metastasis ability of NSCLC cells were analyzed by Transwell assays. Apoptosis assay was used to observe the level of cells apoptosis. The role of CPX in energy metabolism of NSCLC cells was investigated by reactive oxygen species (ROS) detection, glucose uptake, oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) experiments. Western blot was used to examine the protein changes.
We report that CPX inhibits NSCLC cell migration and invasion abilities through inhibiting the epithelial-mesenchymal transition, impairing cellular bioenergetics, and promoting reactive oxygen species to activate endoplasmic reticulum (ER) stress-induced apoptotic cell death. Moreover, CPX intraperitoneal injection can significantly inhibit NSCLC growth in vivo in a xenograft model.
Our study revealed that CPX targets cellular bioenergetics and activates unfolded protein response in ER to drive apoptosis in NSCLC cells, indicating that CPX may be a potential therapeutic drug for the treatment of NSCLC. Video Abstract.
目前，肺癌仍是全球癌症相关死亡的主要原因。将现有药物重新定位用于其他疾病是一种很有前景的癌症治疗策略，这可能会迅速将潜在的有前景的药物推进临床试验，并降低药物开发成本。环吡酮（CPX）是一种常用于治疗真菌感染的铁螯合剂，最近已显示在体外和体内对包括实体瘤和血液系统恶性肿瘤在内的多种癌症具有抗肿瘤活性。然而，CPX对非小细胞肺癌（NSCLC）的作用及其潜在机制仍不清楚。
采用CCK-8、克隆形成试验和细胞周期检测观察抑制剂对NSCLC细胞增殖能力的影响。通过Transwell试验分析CPX对NSCLC细胞转移能力的影响。采用凋亡试验观察细胞凋亡水平。通过活性氧（ROS）检测、葡萄糖摄取、氧消耗率（OCR）和细胞外酸化率（ECAR）实验研究CPX在NSCLC细胞能量代谢中的作用。采用蛋白质免疫印迹法检测蛋白质变化。
我们报告CPX通过抑制上皮-间质转化、损害细胞生物能量学以及促进活性氧激活内质网（ER）应激诱导的凋亡细胞死亡来抑制NSCLC细胞的迁移和侵袭能力。此外，在异种移植模型中，CPX腹腔注射可显著抑制体内NSCLC的生长。
我们的研究表明，CPX靶向细胞生物能量学并激活内质网中的未折叠蛋白反应以驱动NSCLC细胞凋亡，表明CPX可能是治疗NSCLC的潜在治疗药物。视频摘要。
