ABCB1-mediated docetaxel resistance reversed by erastin in prostate cancer

Fangfang Chen, Shiqi Wu, Ni Kuang, Yan Zeng, Meixi Li, Chen Xu
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Abstract

Docetaxel (Doc) currently serves as the primary first-line treatment for patients with castrate-resistant prostate cancer (CRPC). Erastin, a small molecule compound, can trigger inhibition of the cystine–glutamate reverse transport system and other pathways, leading to iron-dependent cell death (ferroptosis). Beyond its role in inducing cancer cell death, erastin demonstrates potential when combined with chemotherapy drugs to heighten cancer cell drug susceptibility. However, the augmentation by erastin of the effects of Doc treatment on prostate cancer, and the underlying mechanisms involved, remain unclear. In the present study, we determined the role and the underlying molecular mechanism of erastin against CRPC. The results showed that CRPC cell lines were resistant to Doc, and the expression of ferroptosis-related factors in drug-resistant cell lines was downregulated. Erastin, in synergy with Doc, exerts a pro-apoptotic effect. Erastin significantly inhibited the activity of ATP-binding cassette subfamily B member 1 (ABCB1) but did not change its protein expression and localization. Finally, in mice, erastin treatment dramatically reduced tumor growth in vivo. Taken together, our findings demonstrate that erastin enhances Doc-induced apoptosis to a certain extent and reverses Doc resistance in prostate cancer by inhibiting the activity of multidrug-resistant protein ABCB1.

Abstract Image

依拉斯汀可逆转前列腺癌中 ABCB1 介导的多西他赛耐药性
多西他赛(Doc)目前是阉割耐药前列腺癌(CRPC)患者的主要一线治疗药物。厄拉斯汀是一种小分子化合物,它能引发对胱氨酸-谷氨酸逆向转运系统和其他途径的抑制,导致铁依赖性细胞死亡(铁变态反应)。除了诱导癌细胞死亡的作用外,厄拉斯特还具有与化疗药物联合使用的潜力,可提高癌细胞对药物的敏感性。然而,厄拉斯特能增强多克治疗对前列腺癌的效果,其潜在机制尚不清楚。在本研究中,我们确定了厄拉斯汀对CRPC的作用及其分子机制。结果表明,CRPC细胞株对Doc具有耐药性,耐药细胞株中的铁突变相关因子表达下调。依拉斯汀与Doc协同发挥了促进细胞凋亡的作用。Erastin 能明显抑制 ATP 结合盒 B 亚家族成员 1(ABCB1)的活性,但不改变其蛋白表达和定位。最后,在小鼠体内,厄拉斯特治疗可大大降低肿瘤的生长。综上所述,我们的研究结果表明,厄拉斯汀能在一定程度上增强Doc诱导的细胞凋亡,并通过抑制多药耐药蛋白ABCB1的活性来逆转前列腺癌对Doc的耐药性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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