Deferasirox’s Anti-Chemoresistance and Anti-Metastatic Effect on Non-Small Cell Lung Carcinoma

• Published in: Biomedicines Vol. 12; no. 10; p. 2272
• Main Authors: Delgado, Yamixa, Torres-Sanchez, Anamaris, Perez, Daraishka, Torres, Grace, Estrada, Sthephanie, Ortiz Alvelo, Natalia, Vega, Jaisy, Santos, Laurie, Torres, Aracelis, Madera, Bismark A., Ferrer-Acosta, Yancy
• Format: Journal Article
• Language: English
• Published: 07.10.2024
• ISSN: 2227-9059; 2227-9059
• DOI: 10.3390/biomedicines12102272

Clinically approved iron chelators, originally designed to address iron overload disorders, have emerged as potential anticancer agents. Deferasirox (Def), a tridentate iron chelator, has demonstrated antiproliferative effects in cancer. Background/Objectives: This study aims to elucidate the mechanism of action of Def and its impact on non-small cell lung carcinoma (NSCLC). Methods: NSCLC A549 cells were treated with Def to assess cytotoxicity, the effect on nuclear and mitochondrial pathways, and iron-containing proteins and genes to evaluate anti-metastasis and chemoresistance. A lung carcinoma mouse model was used for in vivo studies. Results: Our findings revealed that Def induced cytotoxicity, effectively chelated intracellular iron, and triggered apoptosis through the increase in phosphatidylserine externalization and caspase 3 activity. Additionally, Def caused G0/G1 cell cycle arrest by downregulating the ribonucleotide reductase catalytic subunit. Furthermore, Def perturbed mitochondrial function by promoting the production of reactive oxygen species and the inhibition of glutathione as a measurement of ferroptosis activation. Def demonstrated inhibitory effects on cell migration in scratch assays, which was supported by the upregulation of n-myc downstream-regulated gene 1 and downregulation of the epidermal growth factor receptor protein. Also, Def downregulated one of the main markers of chemoresistance, the ABCB1 gene. In vivo experiments using a lung carcinoma mouse model showed that Def treatment did not affect the animal’s body weight and showed a significant decrease in tumor growth. Conclusions: This investigation lays the groundwork for unraveling Def action’s molecular targets and mechanisms in lung carcinoma, particularly within iron-related pathways, pointing out its anti-metastasis and anti-chemoresistance effect.