Dual Functioning Ru(II)/Ir(III) Complexes for Ferroptosis and Apoptosis in Triple Negative Breast Cancer: A Proof of Concept by Glutathione Depletion

IF 3.3 3区化学 Q2 CHEMISTRY, INORGANIC & NUCLEAR

Dalton Transactions Pub Date : 2025-10-02 DOI:10.1039/d5dt01428j

Utpal Das, Tiasha Dasgupta, Krishna Santhoshkumar, Jayaprakash Meena, Annamalai Senthil Kumar, Rajesh Kushwaha, Rishav Das, Debasish Mondal, Kuntal Maji, Prasanta Ghosh, Samya Banerjee, Tamizhselvi Ramasamy, Rinku Chakrabarty, Priyankar Paira

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引用次数: 0

Abstract

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer which lacks effective targeted therapies because of negative expression of the targetable bioreceptors. Fighting with TNBC requires innovative solutions beyond conventional treatments. Herein, we have introduced novel imidazo-phenanthroline-based Ru(II)/Ir(III) complexes that exhibit a dual function on cancer cells by triggering both apoptosis and ferroptosis. By generating a surge of reactive oxygen species (ROS), depleting crucial antioxidants like GSH (Glutathione) and NADPH (nicotinamide adenine dinucleotide phosphate), and disrupting mitochondrial function, these complexes dismantle tumor defenses from within. Mechanistically, these complexes disrupt the antioxidant defense system of tumor cells, reduce mitochondrial membrane potential (MMP), activate Caspase, induce lipid peroxidation (LPO) accumulation, cause mitochondrial shrinkage, and downregulate glutathione peroxidase 4 (GPX4), ultimately leading to cancer cell death.

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双功能Ru(II)/Ir（III）复合物在三阴性乳腺癌中的铁凋亡和细胞凋亡：谷胱甘肽耗竭的概念证明

三阴性乳腺癌（TNBC）是最具侵袭性的乳腺癌亚型，由于可靶向生物受体的阴性表达，缺乏有效的靶向治疗。与TNBC的斗争需要超越传统治疗的创新解决方案。在此，我们引入了新型咪唑-菲罗啉基Ru(II)/Ir（III）配合物，该配合物对癌细胞具有双重功能，可触发细胞凋亡和铁凋亡。通过产生活性氧（ROS）的激增，消耗关键的抗氧化剂，如谷胱甘肽（GSH）和NADPH（烟酰胺腺嘌呤二核苷酸磷酸），并破坏线粒体功能，这些复合物从内部破坏肿瘤防御。在机制上，这些复合物破坏肿瘤细胞的抗氧化防御系统，降低线粒体膜电位（MMP），激活Caspase，诱导脂质过氧化（LPO）积累，导致线粒体收缩，下调谷胱甘肽过氧化物酶4 (GPX4)，最终导致癌细胞死亡。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Dalton Transactions 化学-无机化学与核化学

CiteScore

6.60

自引率

7.50%

发文量

1832

审稿时长

1.5 months

期刊介绍： Dalton Transactions is a journal for all areas of inorganic chemistry, which encompasses the organometallic, bioinorganic and materials chemistry of the elements, with applications including synthesis, catalysis, energy conversion/storage, electrical devices and medicine. Dalton Transactions welcomes high-quality, original submissions in all of these areas and more, where the advancement of knowledge in inorganic chemistry is significant.