Nuclear factor erythroid 2-related factor 2 (Nrf2) significantly contributes to drug resistance of cancer cells, and Nrf2 inhibitors have been vigorously pursued. Repurposing of existing drugs, especially anticancer drugs, is a straightforward and promising strategy to find clinically available Nrf2 inhibitors and effective drug combinations. Topoisomerase inhibitors SN-38 (an active metabolite of irinotecan), topotecan, mitoxantrone, and epirubicin were found to significantly suppress Nrf2 transcriptional activity in cancer cells. SN-38, the most potent one among them, significantly inhibited the transcription of Nrf2, as indicated by decreased mRNA level and binding of RNA polymerase II to NFE2L2 gene, while no impact on Nrf2 protein or mRNA degradation was observed. SN-38 synergized with Nrf2-sensitive anticancer drugs such as mitomycin C in killing colorectal cancer cells, and irinotecan and mitomycin C synergistically inhibited the growth of SW480 xenografts in nude mice. Our study identified SN-38 and three other topoisomerase inhibitors as Nrf2 inhibitors, revealed the Nrf2-inhibitory mechanism of SN-38, and indicate that clinically feasible drug combinations could be designed based on their interactions with Nrf2 signaling.

中文翻译：

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SN-38是伊立替康的活性代谢物，抑制核因子红细胞2相关因子2的转录，增强结直肠癌细胞的药物敏感性

核因子红细胞2相关因子2（Nrf2）显着促进癌细胞的耐药性，Nrf2抑制剂已得到大力研究。重新利用现有药物，特别是抗癌药物，是寻找临床可用的 Nrf2 抑制剂和有效药物组合的一种简单且有前景的策略。拓扑异构酶抑制剂 SN-38（伊立替康的活性代谢物）、拓扑替康、米托蒽醌和表阿霉素被发现可显着抑制癌细胞中的 Nrf2 转录活性。SN-38 是其中最有效的一种，显着抑制 Nrf2 的转录，mRNA 水平降低以及 RNA 聚合酶 II 与 NFE2L2 基因的结合表明，但未观察到对 Nrf2 蛋白或 mRNA 降解的影响。SN-38与Nrf2敏感抗癌药物丝裂霉素C协同杀伤结直肠癌细胞，伊立替康和丝裂霉素C协同抑制裸鼠SW480异种移植瘤的生长。我们的研究将SN-38和其他三种拓扑异构酶抑制剂鉴定为Nrf2抑制剂，揭示了SN-38的Nrf2抑制机制，并表明可以根据它们与Nrf2信号传导的相互作用来设计临床上可行的药物组合。