期刊
CELL CHEMICAL BIOLOGY
卷 25, 期 12, 页码 1456-+出版社
CELL PRESS
DOI: 10.1016/j.chembiol.2018.09.005
关键词
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资金
- Edinburgh Protein Production Facility (EPPF)
- Wellcome Trust [101527/Z/13/Z]
- Zhejiang University School of Medicine
- NIH [R21CA198409, R01CA214567-01, P50 CA174523-02]
- MERIT Award NIH [R37AAA11147]
- EPSRC [EP/N021134/1]
- Veterans Affairs Merit Review Award [5I01BX001228]
- NIH/NCI [R01CA197919]
- European Union's Seventh Framework Program FP7/2007-2013/ERC synergy grant [319661 COMBATCANCER]
- Cancer Research UK [C157/A24837]
- Medical Research Council [MC_PC_U127585840]
- MRC IGMM Translational Science Award
- European Research Council [ZF-MEL-CHEMBIO-648489]
- L'Oreal-Melanoma Research Alliance Team Science Award [401181]
- MRC [MC_UU_00007/9, MC_PC_U127585840] Funding Source: UKRI
- Wellcome Trust [101527/Z/13/Z] Funding Source: Wellcome Trust
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. Wediscover 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 twohit 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 nifuroxazideALDH1 activation goes beyond current strategies based on inhibiting ALDH1 and provides a rational basis for the nifuroxazidemechanismof action in cancer.
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