title: Syrosingopine sensitizes cancer cells to killing by metformin.
abstract: We report that the anticancer activity of the widely used diabetic drug metformin is strongly potentiated by syrosingopine. Synthetic lethality elicited by combining the two drugs is synergistic and specific to transformed cells. This effect is unrelated to syrosingopine's known role as an inhibitor of the vesicular monoamine transporters. Syrosingopine binds to the glycolytic enzyme α-enolase in vitro, and the expression of the γ-enolase isoform correlates with nonresponsiveness to the drug combination. Syrosingopine sensitized cancer cells to metformin and its more potent derivative phenformin far below the individual toxic threshold of each compound. Thus, combining syrosingopine and codrugs is a promising therapeutic strategy for clinical application for the treatment of cancer.
authors.affiliation: Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Don
authors.initials: D
authors.lastname: Benjamin
authors.affiliation: Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Marco
authors.initials: M
authors.lastname: Colombi
authors.affiliation: Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Sravanth K
authors.initials: SK
authors.lastname: Hindupur
authors.affiliation: Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Charles
authors.identifier: 0000-0002-9837-6916
authors.initials: C
authors.lastname: Betz
authors.affiliation: Basilea Pharmaceutica International Ltd., Basel, Switzerland.
authors.forename: Heidi A
authors.identifier: 0000-0003-4721-0411
authors.initials: HA
authors.lastname: Lane
authors.affiliation: Basilea Pharmaceutica International Ltd., Basel, Switzerland.
authors.forename: Mahmoud Y M
authors.identifier: 0000-0001-8914-7970
authors.initials: MY
authors.lastname: El-Shemerly
authors.affiliation: Institute for Medical Microbiology, University of Basel, 4003 Basel, Switzerland.
authors.forename: Min
authors.initials: M
authors.lastname: Lu
authors.affiliation: Molecular Pathology, University Hospital Basel, 4003 Basel, Switzerland.
authors.forename: Luca
authors.identifier: 0000-0001-8249-9914
authors.initials: L
authors.lastname: Quagliata
authors.affiliation: Molecular Pathology, University Hospital Basel, 4003 Basel, Switzerland.
authors.forename: Luigi
authors.initials: L
authors.lastname: Terracciano
authors.affiliation: Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Suzette
authors.initials: S
authors.lastname: Moes
authors.affiliation: Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Timothy
authors.initials: T
authors.lastname: Sharpe
authors.affiliation: Stem Cell Center of Competence, University of Basel, 4056 Basel, Switzerland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Wodnar-Filipowicz
authors.affiliation: Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Christoph
authors.identifier: 0000-0002-4300-9721
authors.initials: C
authors.lastname: Moroni
authors.affiliation: Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Hall
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004357:Drug Synergism; D006019:Glycolysis; D006801:Humans; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D010629:Phenformin / Q000494:pharmacology; D010751:Phosphopyruvate Hydratase / Q000737:chemistry; D012110:Reserpine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D012110:Reserpine; D008687:Metformin; D010629:Phenformin; D010751:Phosphopyruvate Hydratase; C084824:syrosingopine
keywords: Cancer; Mitochondria; biguanide; metabolism; metformin; synthetic lethality; syrosingopine