ALDH1 Bio-activates Nifuroxazide to Eradicate ALDHHigh Melanoma-Initiating Cells

Sana Sarvi, Richard Crispin, Yuting Lu, Lifan Zeng, Thomas 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

4 Citations (Scopus)

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 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 (US)
Pages (from-to)1456-1469.e6
JournalCell Chemical Biology
Volume25
Issue number12
DOIs
StatePublished - Dec 20 2018

Fingerprint

Melanoma
Nitrofurans
Prodrugs
Chemical activation
Neoplasms
Aldehyde Dehydrogenase
Neoplastic Stem Cells
Mitogen-Activated Protein Kinase Kinases
Metabolites
Stem cells
Drug Resistance
aldehyde dehydrogenase 1
nifuroxazide
Tumors
Protein Isoforms
Anti-Bacterial Agents
Mutation
Enzymes
Therapeutics
Pharmaceutical Preparations

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., Houston, D. R., ... Patton, E. E. (2018). ALDH1 Bio-activates Nifuroxazide to Eradicate ALDHHigh Melanoma-Initiating Cells. Cell Chemical Biology, 25(12), 1456-1469.e6. https://doi.org/10.1016/j.chembiol.2018.09.005

ALDH1 Bio-activates Nifuroxazide to Eradicate ALDHHigh Melanoma-Initiating Cells. / Sarvi, Sana; Crispin, Richard; Lu, Yuting; Zeng, Lifan; Hurley, Thomas; Houston, Douglas R.; von Kriegsheim, Alex; Chen, Che Hong; Mochly-Rosen, Daria; Ranzani, Marco; Mathers, Marie E.; Xu, Xiaowei; Xu, Wei; Adams, David J.; Carragher, Neil O.; Fujita, Mayumi; Schuchter, Lynn; Unciti-Broceta, Asier; Brunton, Valerie G.; Patton, E. Elizabeth.

In: Cell Chemical Biology, Vol. 25, No. 12, 20.12.2018, p. 1456-1469.e6.

Research output: Contribution to journalArticle

Sarvi, S, Crispin, R, Lu, Y, Zeng, L, Hurley, T, Houston, DR, von Kriegsheim, A, Chen, CH, Mochly-Rosen, D, Ranzani, M, Mathers, ME, Xu, X, Xu, W, Adams, DJ, Carragher, NO, Fujita, M, Schuchter, L, Unciti-Broceta, A, Brunton, VG & Patton, EE 2018, 'ALDH1 Bio-activates Nifuroxazide to Eradicate ALDHHigh Melanoma-Initiating Cells', Cell Chemical Biology, vol. 25, no. 12, pp. 1456-1469.e6. https://doi.org/10.1016/j.chembiol.2018.09.005
Sarvi, Sana ; Crispin, Richard ; Lu, Yuting ; Zeng, Lifan ; Hurley, Thomas ; Houston, Douglas R. ; von Kriegsheim, Alex ; Chen, Che Hong ; Mochly-Rosen, Daria ; Ranzani, Marco ; Mathers, Marie E. ; Xu, Xiaowei ; Xu, Wei ; Adams, David J. ; Carragher, Neil O. ; Fujita, Mayumi ; Schuchter, Lynn ; Unciti-Broceta, Asier ; Brunton, Valerie G. ; Patton, E. Elizabeth. / ALDH1 Bio-activates Nifuroxazide to Eradicate ALDHHigh Melanoma-Initiating Cells. In: Cell Chemical Biology. 2018 ; Vol. 25, No. 12. pp. 1456-1469.e6.
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AU - Zeng, Lifan

AU - Hurley, Thomas

AU - Houston, Douglas R.

AU - von Kriegsheim, Alex

AU - Chen, Che Hong

AU - Mochly-Rosen, Daria

AU - Ranzani, Marco

AU - Mathers, Marie E.

AU - Xu, Xiaowei

AU - Xu, Wei

AU - Adams, David J.

AU - Carragher, Neil O.

AU - Fujita, Mayumi

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