Browsing by Author "Chen, Che-Hong"

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    ALDH1 Bio-activates Nifuroxazide to Eradicate ALDHHigh Melanoma-Initiating Cells
    (Elsevier, 2018-12-20) Sarvi, Sana; Crispin, Richard; Lu, Yuting; Zeng, Lifan; Hurley, Thomas D.; 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; Biochemistry and Molecular Biology, School of Medicine
    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.
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    Development of Selective Inhibitors for Aldehyde Dehydrogenases Based on Substituted Indole-2,3-diones
    (American Chemical Society, 2014-02-13) Kimble-Hill, Ann C.; Parajuli, Bibek; Chen, Che-Hong; Mochly-Rosen, Daria; Hurley, Thomas D.; Department of Biochemistry & Molecular Biology, IU School of Medicine
    Aldehyde dehydrogenases (ALDH) participate in multiple metabolic pathways and have been indicated to play a role in several cancerous disease states. Our laboratory is interested in developing novel and selective ALDH inhibitors. We looked to further work recently published by developing a class of isoenzyme-selective inhibitors using similar indole-2,3-diones that exhibit differential inhibition of ALDH1A1, ALDH2, and ALDH3A1. Kinetic and X-ray crystallography data suggest that these inhibitors are competitive against aldehyde binding, forming direct interactions with active-site cysteine residues. The selectivity is precise in that these compounds appear to interact directly with the catalytic nucleophile, Cys243, in ALDH3A1 but not in ALDH2. In ALDH2, the 3-keto group is surrounded by the adjacent Cys301/303. Surprisingly, the orientation of the interaction changes depending on the nature of the substitutions on the basic indole ring structure and correlates well with the observed structure–activity relationships for each ALDH isoenzyme.