Wang Sicong, Shan Min, Xu Zhongren, Jiang Guizhi, Wang Mengshi, Zhou Yanyu, Zhao Xiao, Tonissen Kathryn F, Liu Wukun, Di Trapani Giovanna
School of Environment and Science, Griffith University, Brisbane, Qld 4111, Australia; Institute for Biomedicine and Glycomics, Griffith University, Brisbane, Qld 4111, Australia.
Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
J Inorg Biochem. 2025 Nov;272:113004. doi: 10.1016/j.jinorgbio.2025.113004. Epub 2025 Jul 16.
Antioxidant systems, especially the thioredoxin (Trx) and glutathione (GSH) systems, represent promising targets for cancer therapy. Overexpression of these systems has been reported in many cancers, including lymphoma and considered as a mechanism of protection for cancer cells from the high levels of reactive oxygen species (ROS). Over several decades, metal-based complexes including gold complexes such as auranofin have shown anticancer activity by targeting thiols and selenol groups in the active site of thioredoxin reductase (TrxR). However, lack of selectivity, severe side effects or resistance to therapy have been widely reported. Recently, glutathione peroxidase (Gpx) has been reported as one of the key proteins that regulate ferroptosis in cells. To expand the armory for targeting antioxidant systems, in this study eleven new indole-metal complexes were synthesized and assessed for their antiproliferative activity in lymphoma cell lines. The indole‑gold(I)-based complexes showed the best anti-lymphoma activity via inhibiting TrxR and Gpx, but not glutathione reductase (GR), when compared to the indole‑iron-based and cobalt-based complexes. Further investigation revealed that two of the indole‑gold(I)-based complexes, 3h and 3i, induced the expression of ferroptosis-related genes and an increase in lipid peroxidation, indicating activation of ferroptosis in these cells. The in vivo study also revealed that these complexes significantly inhibited angiogenesis by reducing formation of blood vessels in zebra fish embryos. Overall, these results show the potential of 3h and 3i as TrxR and Gpx inhibitors in lymphoma cells, warranting further assessment as anticancer agents and potential inducers of ferroptosis.
抗氧化系统，尤其是硫氧还蛋白（Trx）和谷胱甘肽（GSH）系统，是癌症治疗中很有前景的靶点。在包括淋巴瘤在内的许多癌症中都报道了这些系统的过表达，并且被认为是癌细胞抵御高水平活性氧（ROS）的一种保护机制。几十年来，包括金配合物（如金诺芬）在内的金属基配合物已通过靶向硫氧还蛋白还原酶（TrxR）活性位点中的巯基和硒醇基团显示出抗癌活性。然而，缺乏选择性、严重的副作用或对治疗的耐药性已被广泛报道。最近，谷胱甘肽过氧化物酶（Gpx）被报道为调节细胞铁死亡的关键蛋白之一。为了扩充靶向抗氧化系统的手段，在本研究中合成了11种新型吲哚 - 金属配合物，并评估了它们在淋巴瘤细胞系中的抗增殖活性。与吲哚 - 铁基和钴基配合物相比，基于吲哚 - 金（I）的配合物通过抑制TrxR和Gpx而非谷胱甘肽还原酶（GR）显示出最佳的抗淋巴瘤活性。进一步研究表明，两种基于吲哚 - 金（I）的配合物3h和3i诱导了铁死亡相关基因的表达以及脂质过氧化增加，表明这些细胞中铁死亡被激活。体内研究还表明，这些配合物通过减少斑马鱼胚胎中的血管形成显著抑制了血管生成。总体而言，这些结果表明3h和3i作为淋巴瘤细胞中TrxR和Gpx抑制剂的潜力，值得作为抗癌剂和铁死亡潜在诱导剂进行进一步评估。
