Year: 2018
Type: article
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.
Source: Cell chemical biology
Authors: 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
Institutions: Edinburgh Cancer Research, Institute of Genetics and Cancer, MRC Human Genetics Unit, University of Edinburgh, Indiana University Indianapolis, Indiana University School of Medicine, Stanford Medicine, Stanford University, Wellcome Sanger Institute, Artios Pharma Limited (United Kingdom), Western General Hospital, University of Pennsylvania, Abramson Cancer Center, University of Colorado Anschutz
Language: English
Topic: Cancer Cells and Metastasis
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $6,010
Funders: U.S. Department of Veterans Affairs, Melanoma Research Alliance, University of Pennsylvania, Wellcome Trust, QIMR Berghofer Medical Research Institute, Cancer Research UK, European Commission, Zhejiang University, National Institutes of Health, Medical Research Council, Engineering and Physical Sciences Research Council, European Research Council, National Institute on Alcohol Abuse and Alcoholism, National Cancer Institute, H2020 European Research Council, FP7 Ideas: European Research Council
Awards: G1094896707, G2354850150, Isozyme-selective ALDH Inhibitors for Sensitizing Ovarian Cancer Stem-like Cells to Chemotherapy, G2436052604, The Edinburgh Protein Production Facility (EPPF)., Combination therapies for personalized cancer medicine., G3207356259, Imaging and targeting dormant and pro-metastatic melanoma lesions in vivo, The Edinburgh Protein Production Facility (EPPF)., Modulation of inflammasome-mediated cytokine activation by EGCG in human melanoma., G4616801729, G4759280862, Chemical Biology in Zebrafish: Drug-Leads and New Targets in the Melanocyte Lineage and Melanoma, G5014113351, G5426708721, Mechanisms of Ethanol-Induced Cardiac Protection, G620189191, G6674189921, G7067192677, Palladium-activated prodrug therapy: a novel focal therapy for localised cancers of unmet need, G855513257, G9000003799, G9000022533, G9000200621, G9000294963, Activation and Inhibition of Aldehyde Dehydrogenase 2, G938309714
OpenAlex ID: W2895729583