由于其在调节能量代谢和细胞凋亡中的关键作用，癌细胞中的线粒体被认为是脆弱且可行的靶标。人们发现许多抗癌剂，例如金属化合物，主要针对并干扰线粒体，这可能导致能量代谢紊乱，更重要的是，引发细胞凋亡。在这项工作中，合成了金基复合物 7 (GC7)，并在一系列不同的癌细胞系中进行了评估。测定了 GC7 对细胞活力、细胞凋亡和集落形成的抗癌功效。评估并分析了 GC7 处理后的细胞硫氧还蛋白还原酶 (TrxR) 活性、耗氧率 (OCR)、葡萄糖摄取和乳酸生成。 Jeko-1和A549异种移植模型用于评估GC7的肿瘤抑制作用。结果表明，GC7 具有广谱抗癌作用，在多种癌细胞系中的 IC50 值范围为 0.43 至 1.2 μM，比金基金诺芬更有效（∼2-6 倍）。 GC7（0.3 和 1 μM）可有效诱导 Jeko-1、A549 和 HCT116 细胞凋亡，0.1 μM 时可抑制癌症干细胞 GSC11 和 GSC23 细胞的球形形成，0.3 μM 时可完全消除集落。初步机制研究表明，GC7 抑制细胞 TrxR 活性，抑制线粒体 OCR，降低线粒体膜电位 (MMP)，减少葡萄糖摄取，并可能抑制糖酵解以减少乳酸产生。预计 GC7 具有与金诺芬相似但略有不同的药代动力学特征。最后，GC7（20 mg/kg，口服，5 次/周，或 3 mg/kg，IP，3/周）显着抑制肿瘤生长。总之，GC7 在抑制癌细胞增殖方面显示出巨大潜力，可能是通过抑制 TrxR 和影响线粒体介导的能量代谢来实现的。版权所有 © 2024 Elsevier Ltd。保留所有权利。

Due to their pivotal roles in regulating energy metabolism and apoptosis, mitochondria in cancer cells have been considered a vulnerable and feasible target. Many anticancer agents, e.g., metal-based compounds, are found to target and disturb mitochondria primarily, which may lead to the disturbance of energy metabolism and, more importantly, the initiation of apoptosis. In this work, a gold-based complex 7 (GC7) was synthesized and evaluated in a series of different cancer cell lines. The anticancer efficacies of GC7 on cell viability, apoptosis, and colony formation were determined. Cellular thioredoxin reductase (TrxR) activity, oxygen consumption rate (OCR), glucose uptake, and lactate production following GC7 treatment were evaluated and analyzed. The Jeko-1 and A549 xenograft models were used to assess GC7's tumor-suppressing effects. The results showed that GC7 possessed a broad-spectrum anticancer effect, with IC50 values ranging from 0.43 to 1.2 μM in multiple cancer cell lines, which was more potent than gold-based auranofin (∼2-6 folds). GC7 (0.3 and 1 μM) efficiently induced apoptosis of Jeko-1, A549, and HCT116 cells, and it suppressed the sphere formation of cancer stem cells GSC11 and GSC23 cells at 0.1 μM, and it completely eliminated colony at 0.3 μM. The preliminary mechanistic study showed that GC7 inhibited cellular TrxR activity, suppressed mitochondrial OCR, reduced mitochondrial membrane potential (MMP), decreased glucose uptake, and possibly suppressed glycolysis to reduce lactate production. GC7 was predicted to have a similar yet slightly different pharmacokinetic profile as auranofin. Finally, GC7 (20 mg/kg, oral, 5/week, or 3 mg/kg, IP, 3/week) significantly inhibited tumor growth. In conclusion, GC7 showed great potential in suppressing cancer cell proliferation, probably via inhibiting TrxR and impacting mitochondria-mediated energy metabolism.Copyright © 2024 Elsevier Ltd. All rights reserved.