title: High-throughput screening for growth inhibitors using a yeast model of familial paraganglioma.
abstract: Classical tumor suppressor genes block neoplasia by regulating cell growth and death. A remarkable puzzle is therefore presented by familial paraganglioma (PGL), a neuroendocrine cancer where the tumor suppressor genes encode subunits of succinate dehydrogenase (SDH), an enzyme of the tricarboxylic acid (TCA) cycle of central metabolism. Loss of SDH initiates PGL through mechanisms that remain unclear. Could this metabolic defect provide a novel opportunity for chemotherapy of PGL? We report the results of high throughput screening to identify compounds differentially toxic to SDH mutant cells using a powerful S. cerevisiae (yeast) model of PGL. Screening more than 200,000 compounds identifies 12 compounds that are differentially toxic to SDH-mutant yeast. Interestingly, two of the agents, dequalinium and tetraethylthiuram disulfide (disulfiram), are anti-malarials with the latter reported to be a glycolysis inhibitor. We show that four of the additional hits are potent inhibitors of yeast alcohol dehydrogenase. Because alcohol dehydrogenase regenerates NAD(+) in glycolytic cells that lack TCA cycle function, this result raises the possibility that lactate dehydrogenase, which plays the equivalent role in human cells, might be a target of interest for PGL therapy. We confirm that human cells deficient in SDH are differentially sensitive to a lactate dehydrogenase inhibitor.
authors: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America.
authors: Irina
authors: I
authors: Bancos
authors: John Paul
authors: JP
authors: Bida
authors: Defeng
authors: D
authors: Tian
authors: Mary
authors: M
authors: Bundrick
authors: Kristen
authors: K
authors: John
authors: Molly Nelson
authors: MN
authors: Holte
authors: Yeng F
authors: YF
authors: Her
authors: Debra
authors: D
authors: Evans
authors: Dyana T
authors: DT
authors: Saenz
authors: Eric M
authors: EM
authors: Poeschla
authors: Derek
authors: D
authors: Hook
authors: Gunda
authors: G
authors: Georg
authors: L James
authors: LJ
authors: Maher
mesh_terms: D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005690:Galactose / Q000378:metabolism; D006131:Growth Inhibitors / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors; D008962:Models, Theoretical; D010235:Paraganglioma / Q000201:enzymology; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000201:enzymology; D013385:Succinate Dehydrogenase / Q000235:genetics
chemical_list: D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D007770:L-Lactate Dehydrogenase; D013385:Succinate Dehydrogenase; D005690:Galactose