Abstract：
Glutathione peroxidase 4 (GPX4) is a promising anticancer therapeutic target; however, the application of GPX4 inhibitors (GPX4i) is limited owing to intrinsic or acquired drug resistance. Hence, understanding the mechanisms underlying drug resistance and discovering molecules that can overcome drug resistance are crucial. Herein, we demonstrated that GPX4i killed bladder cancer cells by inducing lipid reactive oxygen species-mediated ferroptosis and apoptosis, and cisplatin-resistant bladder cancer cells were also resistant to GPX4i, representing a higher half-maximal inhibitory concentration value than that of parent bladder cancer cells. In addition, thioredoxin reductase 1 (TrxR1) overexpression was responsible for GPX4i resistance in cisplatin-resistant bladder cancer cells, and inhibiting TrxR1 restored the sensitivity of these cells to GPX4i. In vitro and in vivo studies revealed that Jolkinolide B (JB), a natural diterpenoid and previously identified as a TrxR1 inhibitor, potentiated the antiproliferative efficacy of GPX4i (RSL3 and ML162) against cisplatin-resistant bladder cancer cells. Furthermore, GPX4 knockdown and inhibition could augment JB-induced paraptosis and apoptosis. Our results suggest that inhibiting TrxR1 can effectively improve GPX4 inhibition-based anticancer therapy. A combination of JB and GPX4i, which is well-tolerated and has several anticancer mechanisms, may serve as a promising therapy for treating bladder cancer.
摘要：
谷胱甘肽过氧化物酶4(GPX4)是一个很有前途的抗癌治疗靶点;然而,GPX4抑制剂(GPX4i)的应用由于固有或获得性耐药性而受到限制。因此，了解潜在的耐药机制和发现可以克服耐药的分子是至关重要的。在这里，我们证明GPX4i通过诱导脂质活性氧介导的铁凋亡和凋亡来杀死膀胱癌细胞，顺铂耐药的膀胱癌细胞也对GPX4i耐药，代表比亲本膀胱癌细胞更高的半最大抑制浓度值。此外,硫氧还蛋白还原酶1（TrxR1）过表达是导致顺铂耐药膀胱癌细胞中GPX4i耐药的原因，和抑制TrxR1恢复了这些细胞对GPX4i的敏感性。体外和体内研究表明，JolkinolideB(JB)，一种天然的二萜，以前被鉴定为TrxR1抑制剂，增强了GPX4i（RSL3和ML162）对顺铂耐药的膀胱癌细胞的抗增殖功效。此外，GPX4的敲除和抑制可以增加JB诱导的凋亡和凋亡。我们的结果表明，抑制TrxR1可以有效改善基于GPX4抑制的抗癌治疗。JB和GPX4i的组合，它具有良好的耐受性，并具有多种抗癌机制，可能是治疗膀胱癌的一种有希望的疗法。
