SN‐38, an active metabolite of irinotecan, inhibits transcription of nuclear factor erythroid 2‐related factor 2 and enhances drug sensitivity of colorectal cancer cells

Abstract

AbstractNuclear 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.