许多实体瘤（包括非小细胞肺癌（NSCLC））的治疗方法主要基于使用含铂抗癌药物，并且通常具有对该药物的获得性或内在耐药性的特征。因此，寻找更安全、更有效的药物仍然是一个公开的挑战。两种有机金属钌(II)环戊二烯基化合物 [Ru(η5-C5H4CHO)(Me2bipy)(PPh3)] (RT150) 和 [Ru(η5-C5H4CH2OH)(Me2bipy) (PPh3)][CF3SO3] (RT151) 进行了测试一组顺铂耐药的 NSCLC 细胞系和异种移植物。它们在诱导氧化应激和 DNA 损伤、影响细胞周期并引起细胞凋亡方面比顺铂更有效。重要的是，它们被发现是药物外流转运蛋白的抑制剂。由于这一特性，这些化合物显着增加了 NSCLC 细胞内顺铂的保留和细胞毒性。值得注意的是，它们在体外对非转化细胞（红细胞、成纤维细胞、支气管上皮细胞、心肌细胞和内皮细胞）没有表现出高毒性。两种化合物均诱导血管舒张并减少内皮细胞迁移，表明潜在的抗血管生成特性。 RT151 证实了其对顺铂耐药的 NSCLC 异种移植物的功效。无论是单独使用还是与低剂量顺铂联合使用，RT151 在肝脏、肾脏、脾脏、肺和肿瘤中均显示出良好的生物分布特征。血液化学分析和死后器官病理学证实了该化合物在体内的安全性，即使与顺铂联合使用也是如此。综上所述，我们已经证实了一类新型药物对抗顺铂耐药 NSCLC 的有效性。此外，它们还具有良好的生物相容性和安全性。版权所有 © 2024 作者。由爱思唯尔有限公司出版。保留所有权利。

The therapeutic approach to many solid tumors, including non-small cell lung cancer (NSCLC), is mainly based on the use of platinum-containing anticancer agents and is often characterized by acquired or intrinsic resistance to the drug. Therefore, the search for safer and more effective drugs is still an open challenge. Two organometallic ruthenium(II) cyclopentadienyl compounds [Ru(η5-C5H4CHO)(Me2bipy)(PPh3)]+ (RT150) and [Ru(η5-C5H4CH2OH)(Me2bipy) (PPh3)][CF3SO3] (RT151) were tested against a panel of cisplatin-resistant NSCLC cell lines and xenografts. They were more effective than cisplatin in inducing oxidative stress and DNA damage, affecting the cell cycle and causing apoptosis. Importantly, they were found to be inhibitors of drug efflux transporters. Due to this property, the compounds significantly increased the retention and cytotoxicity of cisplatin within NSCLC cells. Notably, they did not display high toxicity in vitro against non-transformed cells (red blood cells, fibroblasts, bronchial epithelial cells, cardiomyocytes, and endothelial cells). Both compounds induced vasorelaxation and reduced endothelial cell migration, suggesting potential anti-angiogenic properties. RT151 confirmed its efficacy against NSCLC xenografts resistant to cisplatin. Either alone or combined with low doses of cisplatin, RT151 showed a good biodistribution profile in the liver, kidney, spleen, lung, and tumor. Hematochemical analysis and post-mortem organ pathology confirmed the safety of the compound in vivo, also when combined with cisplatin. To sum up, we have confirmed the effectiveness of a novel class of drugs against cisplatin-resistant NSCLC. Additionally, they have a good biocompatibility and safety profile.Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.