Front Oncol
Department of Radiation Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Published: February 2022
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 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 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 TOP2A, suggesting CPX could potentially function as a promising chemotherapeutic for LUAD treatment.
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http://dx.doi.org/10.3389/fonc.2022.791916 | DOI Listing |
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