Ferroptosis as a Potential Cell Death Mechanism against Cisplatin-Resistant Lung Cancer Cell Line

Abstract

Purpose: Drug resistance is a challenging issue in cancer chemotherapy. Cell death induction is one of the main strategies to overcome chemotherapy resistance. Notably, ferroptosis has been considered a critical cell death mechanism in recent years. Accordingly, in this study, the different cell death strategies focused on ferroptosis have been utilized to overcome cisplatin resistance in an in vitro lung cancer model. Methods: The physiological functions of Akt1 and GPX4, as critical targets for ferroptosis and apoptosis induction, were suppressed by siRNA or antagonistic agents in resistant A549 cells. Afterward, the interventions' impacts on cell viability, reactive oxygen species (ROS) amount were analyzed by flow cytometry. Moreover, the alteration in the relevant gene and protein expression levels were quantified using Real-time PCR and western blot methods. Results: The result showed that the treatment with Akt1 siRNA reversed the cisplatin resistance in the A549 cell line through the induction of apoptosis. Likewise, the combination treatment of the GPX4 siRNA or FIN56 as Ferroptosis inducers alongside cisplatin elevated ROS's cellular level, reduced the cellular antioxidant genes level, and increased the cisplatin cytotoxic effect. Conclusion: In conclusion, our study indicated that ferroptosis induction can be considered a promising cell death strategy in cisplatin-resistant cancer cells.

Ferroptosis: emerging roles in lung cancer and potential implications in biological compounds

“…By accelerating ferroptosis progress, the development of lung cancer can be suppressed, while the drug resistance and radiation resistance of lung cancer is also resisted to a certain extent ( Mou et al, 2019 ). Studies have shown that achieving ferroptosis increases ROS levels in cells and the cytotoxicity of cisplatin ( Golbashirzadeh et al, 2023 ). Nevertheless, osimertinib-resistant cells are prone to ferroptosis due to raised accumulation of ferrous ions ( Konishi et al, 2023 ).…”

Competing endogenous RNA networks and ferroptosis in cancer: novel therapeutic targets

“…In addition, etoposide-mediated metabolic reprogramming can increase lactate production in NSCLC cells, leading to GPX4 ubiquitination and ferroptosis resistance [ 99 ]. Ferroptosis stimulation via GPX4 knockdown or FIN56 administration can eliminate chemoresistant NSCLC cells [ 100 ]. In line with this, it has been shown that KLF11 suppresses GPX4 in lung adenocarcinoma, stimulates ferroptosis, and enhances their chemosensitivity to cisplatin [ 101 ].…”

Inducing ferroptosis by traditional medicines: a novel approach to reverse chemoresistance in lung cancer

“…Functioning as a type 3 ferroptosis inducer, the ferroptosis-inducing agent 56 (FIN56) promotes ferroptosis by facilitating the autophagydependent protein degradation of GPX4 (Shimada et al, 2016;. FIN56 combined with cisplatin increases cellular ROS levels, decreases antioxidant gene expression, and boosts the cisplatin cytotoxic effect in the A549 cell line, indicating that inducing ferroptosis is a promising strategy in cisplatin-resistant cancer cells (Golbashirzadeh et al, 2023).…”