Screening for Potential Therapeutic Agents for Non-Small Cell Lung Cancer by Targeting Ferroptosis

Abstract

Ferroptosis is a form of non-apoptotic and iron-dependent cell death originally identified in cancer cells. Recently, emerging evidence showed that ferroptosis-targeting therapy could be a novel promising anti-tumour treatment. However, systematic analyses of ferroptosis-related genes for the prognosis of non-small cell lung cancer (NSCLC) and the development of antitumor drugs exploiting the ferroptosis process remain rare. This study aimed to identify genes related to ferroptosis and NSCLC and to initially screen lead compounds that induce ferroptosis in tumor cells. We downloaded mRNA expression profiles and NSCLC clinical data from The Cancer Genome Atlas database to explore the prognostic role of ferroptosis-related genes. Four prognosis-associated ferroptosis-related genes were screened using univariate Cox regression analysis and the lasso Cox regression analysis, which could divide patients with NSCLC into high- and low-risk groups. Then, based on differentially expressed risk- and ferroptosis-related genes, the negatively correlated lead compound flufenamic acid (FFA) was screened through the Connective Map database. This project confirmed that FFA induced ferroptosis in A549 cells and inhibited growth and migration in a dose-dependent manner through CCK-8, scratch, and immunofluorescence assays. In conclusion, targeting ferroptosis might be a therapeutic alternative for NSCLC.

SETD1A‐mediated H3K4me3 methylation upregulates lncRNA HOXC‐AS3 and the binding of HOXC‐AS3 to EP300 and increases EP300 stability to suppress the ferroptosis of NSCLC cells

“…Although a cure for advanced NSCLC is often difficult to achieve owing to drug resistance and poor prognosis, the development of new molecular‐targeted therapies provides patients with hopes of long‐term survival 24 . Targeting ferroptosis represents a new antitumor therapy and ferroptosis‐associated genes allow for effective NSCLC treatment 25 . Reportedly, SETD1A has the potential to be a drug target for lung cancer 9 .…”

“…24 Targeting ferroptosis represents a new antitumor therapy and ferroptosis-associated genes allow for effective NSCLC treatment. 25 Reportedly, SETD1A has the potential to be a drug target for lung cancer. 9 The current study underscored that SETD1-mediated H3K4me3 modification upregulates lncRNA HOXC-AS3 and thereafter enhances the binding of HOXC-AS3 to EP300 and increasing EP300 stability, thus suppressing the ferroptosis of NSCLC cells (Figure 7).…”

Widely targeted metabolomics reveals the antioxidant and anticancer activities of different colors of Dianthus caryophyllus

“…For the detection of CCK-8, we referenced to the method reported by Zhao et al (22). A549 cells and osteosarcoma cells (U2OS) were routinely grown in RPMI-1640 medium supplemented with 10% fetal bovine serum and 1% penicillinstreptomycin, digested and passaged, and plated in a 96 well plate supplemented with 1 × 10 4 cells/well.…”