ALDH1 Bio-activates Nifuroxazide to Eradicate ALDH High 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 journalArticle

10 Scopus citations

Abstract

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 ALDH1 High melanoma cells are sensitive to nifuroxazide, while ALDH1A3 loss-of-function mutations confer drug resistance. In tumors, nifuroxazide targets ALDH1 High 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 ALDH1 High 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 (US)
Pages (from-to)1456-1469.e6
JournalCell Chemical Biology
Volume25
Issue number12
DOIs
StatePublished - Dec 20 2018

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Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

Cite this

Sarvi, S., Crispin, R., Lu, Y., Zeng, L., Hurley, T. D., Houston, D. R., von Kriegsheim, A., Chen, C. H., Mochly-Rosen, D., Ranzani, M., Mathers, M. E., Xu, X., Xu, W., Adams, D. J., Carragher, N. O., Fujita, M., Schuchter, L., Unciti-Broceta, A., Brunton, V. G., & Patton, E. E. (2018). ALDH1 Bio-activates Nifuroxazide to Eradicate ALDH High Melanoma-Initiating Cells Cell Chemical Biology, 25(12), 1456-1469.e6. https://doi.org/10.1016/j.chembiol.2018.09.005