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
Biochemistry & Pharmacology Department, San Juan Bautista School of Medicine, Caguas, PR 00725, USA.
Biology Department, University of Puerto Rico-Rio Piedras, San Juan, PR 00925, USA.
Biomedicines. 2024 Oct 7;12(10):2272. 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. : This study aims to elucidate the mechanism of action of Def and its impact on non-small cell lung carcinoma (NSCLC). : 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. : 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 and downregulation of the epidermal growth factor receptor protein. Also, Def downregulated one of the main markers of chemoresistance, the 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. : 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.
临床批准的铁螯合剂最初是为解决铁过载疾病而设计的，现已成为潜在的抗癌药物。去铁胺（Def）是一种三齿铁螯合剂，已在癌症中显示出抗增殖作用。本研究旨在阐明Def的作用机制及其对非小细胞肺癌（NSCLC）的影响。用Def处理NSCLC A549细胞以评估细胞毒性、对核和线粒体途径的影响以及含铁蛋白质和基因，以评估抗转移和化疗耐药性。使用肺癌小鼠模型进行体内研究。我们的研究结果表明，Def诱导细胞毒性，有效螯合细胞内铁，并通过增加磷脂酰丝氨酸外化和半胱天冬酶3活性触发细胞凋亡。此外，Def通过下调核糖核苷酸还原酶催化亚基导致G0/G1细胞周期停滞。此外，Def通过促进活性氧的产生和抑制谷胱甘肽作为铁死亡激活的指标来扰乱线粒体功能。Def在划痕试验中对细胞迁移表现出抑制作用，这得到了表皮生长因子受体蛋白的上调和下调的支持。此外，Def下调了化疗耐药性的主要标志物之一——基因。使用肺癌小鼠模型的体内实验表明，Def治疗不影响动物体重，并显著降低肿瘤生长。这项研究为揭示Def在肺癌中的作用分子靶点和机制奠定了基础，特别是在与铁相关的途径中，指出了其抗转移和抗化疗耐药性的作用。
