ALDH1 bio-activates nifuroxazide to eradicate ALDHHigh melanoma-initiating cells

Sana Sarvi, Richard Crispin, Yuting Lu, Lifan Zeng, Thomas D Hurley, Douglas R. Houston, Alex von Kriegsheim, Che-Hong Chen, Daria Mochly-Rosen, Marco Ranzani, Marie E. Mathers, Xiaowei Xu, Wei Xu, David J. Adams, Neil O. Carragher, Mayumi Fujita, Lynn Schuchter, Asier Unciti-Broceta, Valerie G. Brunton, E. Elizabeth Patton

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

5-Nitrofurans are antibiotic pro-drugs that have potential as cancer therapeutics. Here, we show that 5-nitrofurans can be bio-activated by aldehyde dehydrogenase (ALDH) 1A1/1A3 enzymes that are highly expressed in a subpopulation of cancer-initiating (stem) cells. We discover that the 5-nitrofuran, nifuroxazide, is selective for bio-activation by ALDH1 isoforms over ALDH2, whereby it both oxidizes ALDH1 and is converted to cytotoxic metabolites in a two-hit pro-drug mechanism. We show that ALDH1High melanoma cells are sensitive to nifuroxazide, while ALDH1A3 loss-of-function mutations confer drug resistance. In tumors, nifuroxazide targets ALDH1High melanoma subpopulations with the subsequent loss of melanoma-initiating cell potential. BRAF and MEK inhibitor therapy increases ALDH1 expression in patient melanomas, and effectively combines with nifuroxazide in melanoma cell models. The selective eradication of ALDH1High cells by nifuroxazide-ALDH1 activation goes beyond current strategies based on inhibiting ALDH1 and provides a rational basis for the nifuroxazide mechanism of action in cancer.
Original languageEnglish
Pages (from-to)1456-1469.e6
Number of pages20
JournalCell Chemical Biology
Issue number12
Early online date4 Oct 2018
Publication statusPublished - 20 Dec 2018

Keywords / Materials (for Non-textual outputs)

  • 5-nitrofurans
  • ALDH
  • BRAF inhibitor
  • cancer stem cells
  • drug mechanism of action
  • drug targets
  • melanoma
  • nifuroxazide
  • pro-drugs
  • tumor-initiating cells


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