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

Cell chemical biology 2018 Dec 20

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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. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Citation

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. ALDH1 Bio-activates Nifuroxazide to Eradicate ALDHHigh Melanoma-Initiating Cells. Cell chemical biology. 2018 Dec 20;25(12):1456-1469.e6