High-grade serous ovarian cancer (HGSOC) accounts for 70% of ovarian cancer cases, and the survival rate remains remarkably low due to the lack of effective long-term consolidation therapies. Clinical remission can be temporarily induced by platinum-based chemotherapy, but death subsequently results from the extensive growth of a platinum-resistant component of the tumor. This work explores a novel treatment against HGSOC using the gold complex auranofin (AF). AF primarily functions as a pro-oxidant by inhibiting thioredoxin reductase (TrxR), an antioxidant enzyme overexpressed in ovarian cancer. We investigated the effect of AF on TrxR activity and the various mechanisms of cytotoxicity using HGSOC cells that are clinically sensitive or resistant to platinum. In addition, we studied the interaction between AF and another pro-oxidant, L-buthionine sulfoximine (L-BSO), an anti-glutathione (GSH) compound. We demonstrated that AF potently inhibited TrxR activity and reduced the vitality and viability of HGSOC cells regardless of their sensitivities to platinum. We showed that AF induces the accumulation of reactive oxygen species (ROS), triggers the depolarization of the mitochondrial membrane, and kills HGSOC cells by inducing apoptosis. Notably, AF-induced cell death was abrogated by the ROS-scavenger N-acetyl cysteine (NAC). In addition, the lethality of AF was associated with the activation of caspases-3/7 and the generation of DNA damage, effects that were also prevented by the presence of NAC. Finally, when AF and L-BSO were combined, we observed synergistic lethality against HGSOC cells, which was mediated by a further increase in ROS and a decrease in the levels of the antioxidant GSH. In summary, our results support the concept that AF can be used alone or in combination with L-BSO to kill HGSOC cells regardless of their sensitivity to platinum, suggesting that the depletion of antioxidants is an efficient strategy to mitigate the course of this disease.
高级别浆液性卵巢癌占卵巢癌病例的70%，由于缺乏有效的长期巩固疗法，其生存率仍然极低。铂类化疗可暂时诱导临床缓解，但随后肿瘤的铂耐药成分广泛生长导致患者死亡。本研究探索使用金复合物金诺芬治疗高级别浆液性卵巢癌的新疗法。金诺芬主要通过抑制硫氧还蛋白还原酶发挥促氧化作用，该抗氧化酶在卵巢癌中过度表达。我们利用临床对铂敏感或耐药的高级别浆液性卵巢癌细胞，研究了金诺芬对硫氧还蛋白还原酶活性的影响及其多种细胞毒性机制。此外，我们还研究了金诺芬与另一种促氧化剂L-丁硫氨酸-亚砜亚胺（一种抗谷胱甘肽化合物）的相互作用。研究证明，无论细胞对铂的敏感性如何，金诺芬都能有效抑制硫氧还蛋白还原酶活性，降低高级别浆液性卵巢癌细胞的活力与生存能力。我们发现金诺芬可诱导活性氧积累，引发线粒体膜去极化，并通过诱导细胞凋亡杀死高级别浆液性卵巢癌细胞。值得注意的是，活性氧清除剂N-乙酰半胱氨酸能够完全阻断金诺芬诱导的细胞死亡。此外，金诺芬的致死效应与caspase-3/7的激活及DNA损伤的产生相关，这些效应同样可被N-乙酰半胱氨酸阻断。最后，当金诺芬与L-丁硫氨酸-亚砜亚胺联合使用时，我们观察到对高级别浆液性卵巢癌细胞的协同致死作用，该作用通过进一步增加活性氧水平和降低抗氧化剂谷胱甘肽水平实现。总之，我们的研究结果支持以下观点：无论高级别浆液性卵巢癌细胞对铂的敏感性如何，金诺芬均可单独或与L-丁硫氨酸-亚砜亚胺联用杀死这些细胞，这表明消耗抗氧化剂是缓解该疾病进展的有效策略。
肿瘤(癌症)患者之家