Nrf2 depletion sensitizes pancreatic cancer cells to gemcitabine via aldehyde dehydrogenase 3a1 repression.

The central regulator of oxidative stress responses, Nrf2, is attracting great interest as a therapeutic target in various cancers. Explorations of novel Nrf2 inhibitors have been reported, which suggest future clinical applications. Halofuginone, the derivative of natural plant alkaloid, has been reported to deplete Nrf2 rapidly in cancer cells with Nrf2 activation. In the current study, we identified that halofuginone sensitizes pancreatic cancer cells to gemcitabine, both in vitro and in vivo settings. We identified downregulation of Aldh3a1 in mouse pancreatic cancer cell lines after halofuginone treatment. The Nrf2 inducer diethyl maleate treatment upregulated Aldh3a1, and Nrf2 deleted pancreatic cancer cell lines failed to show induction. Knockdown of Aldh3a1 also sensitized cancer cells to gemcitabine, suggesting contribution of Aldh3a1 to gemcitabine resistance as a downstream target of Nrf2. Current study confirmed the therapeutic benefits of halofuginone in pancreatic cancer. Mouse cancer cell (K5, K6) were treated with control (DMSO) (K5C, K6C) or halofuginone at 100 nM for 24 hours (K5H, K6H). Gene expression profiles were compared between K5C and K5F, K6C and K6F, respectively.