Pang Yuru, Meng Qiqi, Cui Yangchen, Liu Shiyi, Jiang Huihui, Xu Chenlan, An Yan, Jiao Yang, Zhang Qi, Nie Jihua
Department of Toxicology, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu, China.
State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, China.
Front Pharmacol. 2025 Mar 27;16:1562228. doi: 10.3389/fphar.2025.1562228. eCollection 2025.
Lung cancer is the leading cause of cancer-related death in the worldwide. Although cisplatin and other platinum-based drugs are widely used as radiosensitizers in radiotherapy and considered the first-line treatment for advanced lung cancer, their clinical utility is often limited by drug resistance and severe cytotoxic side effects. In recent years, iridium-based complexes and other transition metal cation complexes with similar structural properties have garnered increasing research interest due to their potential anticancer properties.
Recently, we synthesized a novel iridium (III) complex (Ir-1) and evaluated its safety and stability. The present study aimed to identify Ir-1 with potent anticancer activity by assessing its cytotoxic effects on lung cancer cells in vitro. Additionally, it investigated Ir-1's radiosensitizing efficacy and the underlying mechanisms.
The results demonstrated that Ir-1 exhibited significant radiosensitizing effects on lung cancer cells. Ir-1 effectively reduced cell viability and colony formation, arrested the cell cycle at the G2/M phase, inhibited cell migration and invasion, decreased mitochondrial membrane potential, and increased reactive oxygen species (ROS) generation in lung cancer cells. Importantly, these cytotoxic effects were selective, with minimal impact on normal cells. Mechanistic studies showed that Ir-1 enhanced radiation-induced cancer cell death by disrupting mitochondrial function and activating the mitochondrial apoptotic pathway. This was evidenced by upregulated expression levels of Bax, Cytochrome c (Cyt-C), and Caspase9 proteins, along with reduced level of Bcl-2 protein. Notably, the addition of a Cyt-C inhibitor significantly reduced the expression of Cyt-C and Caspase9 proteins. Similarly, treatment with the Caspase9 inhibitor Z-LEHD-FMK also reduced Caspase9 protein level.
This study provides robust evidence that Ir-1 is a promising and safe radiosensitizer for lung cancer therapy. Its ability to enhance radiation-induced cytotoxicity through mitochondrial dysfunction and activation of apoptotic pathways highlights its potential for clinical application.
肺癌是全球癌症相关死亡的主要原因。尽管顺铂和其他铂类药物在放射治疗中被广泛用作放射增敏剂，并被视为晚期肺癌的一线治疗药物，但其临床应用常常受到耐药性和严重细胞毒性副作用的限制。近年来，基于铱的配合物和其他具有相似结构性质的过渡金属阳离子配合物因其潜在的抗癌特性而受到越来越多的研究关注。
最近，我们合成了一种新型铱（III）配合物（Ir-1）并评估了其安全性和稳定性。本研究旨在通过评估其对肺癌细胞的体外细胞毒性作用来鉴定具有强大抗癌活性的Ir-1。此外，还研究了Ir-1的放射增敏效果及其潜在机制。
结果表明，Ir-1对肺癌细胞表现出显著的放射增敏作用。Ir-1有效降低细胞活力和集落形成，使细胞周期停滞在G2/M期，抑制细胞迁移和侵袭，降低线粒体膜电位，并增加肺癌细胞中活性氧（ROS）的产生。重要的是，这些细胞毒性作用具有选择性，对正常细胞的影响最小。机制研究表明，Ir-1通过破坏线粒体功能和激活线粒体凋亡途径增强辐射诱导的癌细胞死亡。这通过Bax、细胞色素c（Cyt-C）和Caspase9蛋白表达水平上调以及Bcl-2蛋白水平降低得到证明。值得注意的是，添加Cyt-C抑制剂显著降低了Cyt-C和Caspase9蛋白的表达。同样，用Caspase9抑制剂Z-LEHD-FMK处理也降低了Caspase9蛋白水平。
本研究提供了有力证据，表明Ir-1是一种有前景且安全的肺癌治疗放射增敏剂。其通过线粒体功能障碍和凋亡途径激活增强辐射诱导的细胞毒性的能力突出了其临床应用潜力。
