AUTHOR=Yin Jie , Che Gang , Jiang Kan , Zhou Ziyang , Wu Lingyun , Xu Mengyou , Liu Jian , Yan Senxiang 

TITLE=Ciclopirox Olamine Exerts Tumor-Suppressor Effects via Topoisomerase II Alpha in Lung Adenocarcinoma

JOURNAL=Frontiers in Oncology

VOLUME=Volume 12 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.791916

DOI=10.3389/fonc.2022.791916

ISSN=2234-943X

ABSTRACT=Background: Globally, lung cancer is one of the most malignant tumors, of which lung adenocarcinoma (LUAD) is the most common subtype, with a particularly poor prognosis. Ciclopirox olamine (CPX) is an antifungal drug and was recently identified as a potential antitumor agent. However, how CPX and its mechanism of action function during LUAD remain unclear. 
Methods: The effects of CPX on cell proliferation, cell cycle, reactive oxygen species (ROS) levels, and apoptosis were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, colony formation, western blotting, flow cytometry assays, and immunohistochemistry. Global gene expression levels were compared between control and CPX-treated LUAD cells. A LUAD xenograft mouse model was used to evaluate the potential in vivo effects of CPX. 
Results: We observed that CPX displayed strong antitumorigenic properties in LUAD cells, inhibited LUAD proliferation, induced ROS production, caused DNA damage, and activated the ATR-CHK1-P53 pathway. Topoisomerase II alpha (TOP2A) is overexpressed in LUAD and associated with a poor prognosis. By analyzing differentially expressed genes (DEGs), TOP2A was significantly down-regulated in CPX-treated LUAD cells. Furthermore, CPX treatment substantially inhibited in vivo LUAD xenograft growth without toxicity or side effects to the hematological system and internal organs. 
Conclusions: Collectively, for the first time, we showed that CPX exerted tumor-suppressor effects in LUAD via TOP2A, suggesting CPX could potentially function as a promising chemotherapeutic for LUAD treatment.