%0 Journal Article %T Impact of cyclometalated ruthenium(II) complexes on lactate dehydrogenase activity and cytotoxicity in gastric and colon cancer cells %+ Instituto de Química [México, Mexico] %+ Department of Chemistry [Pittsburgh, PA, USA] %+ Equipe 2 "Réponse au Stress Cellulaire & Thérapies Innovantes" / "Stress Response & Innovative Therapies" (STREINTH - Inserm U1113) %+ Service d'oncologie médicale [CHU Strasbourg] %+ Interface de Recherche Fondamentale et Appliquée en Cancérologie (IRFAC - Inserm U1113) %A Rico Bautista, Hugo %A Saavedra Díaz, Rafael Omar %A Shen, Longzhu %A Orvain, Christophe %A Gaiddon, Christian %A Le Lagadec, Ronan %A Ryabov, Alexander %Z We thank financial support from Consejo Nacional de Ciencia y Tecnología (Project 153151 and scholarship 245377 to Hugo Rico Bautista), DGAPA (PAPIIT project IN-207316), ARC, Ligue Contre le Cancer, CNRS, and European Cooperation in Science and Technology action CM1105. %< avec comité de lecture %@ 0162-0134 %J Journal of Inorganic Biochemistry %I Elsevier %V 163 %P 28-38 %8 2016-10 %D 2016 %R 10.1016/j.jinorgbio.2016.07.014 %M 27513948 %K Cyclometalation %K Cytotoxicity %K Enzyme inhibition %K Lactate dehydrogenase %K Molecular docking %K Ruthenium %Z Life Sciences [q-bio] %Z Life Sciences [q-bio]/Cancer %Z Life Sciences [q-bio]/Biochemistry, Molecular Biology %Z Life Sciences [q-bio]/Cellular Biology %Z Life Sciences [q-bio]/Pharmaceutical sciencesJournal articles %X Lactate dehydrogenase (LDH) is a redox enzyme often overexpressed in cancer cells allowing their survival in stressful metabolic tumor environment. Ruthenium(II) complexes have been shown to impact on the activity of purified horseradish peroxidase and glucose oxidase but the physiological relevance remains unclear. In this study we investigated how ruthenium complexes impact on the activity of LDH in vitro and in cancer cells and performed a comparative study using polypyridine ruthenium(II) complex [Ru(bpy)3]2+ (1) and its structurally related cyclometalated 2-phenylpyridinato counterpart [Ru(phpy)(bpy)2]+ (2) (bpy=2,2'-bipyridine, phpyH=2-phenylpyridine). We show that the cytotoxicity in gastric and colon cancer cells induced by 2 is significantly higher compared to 1. The kinetic inhibition mechanisms on purified LDH and the corresponding inhibition constants Ki or i0.5 values were calculated. Though complexes 1 and 2 are structurally very similar (one Ru-C bond in 2 replaces one Ru-N bond in 1), their inhibition modes are different. Cyclometalated complex 2 behaves exclusively as a non-competitive inhibitor of LDH from rabbit muscle (LDHrm), strongly suggesting that 2 does not interact with LDH in the vicinities of either lactate/pyruvate or NAD+/NADH binding sites. Sites of interaction of 1 and 2 with LDHrm were revealed theoretically through computational molecular docking. Inhibition of LDH activity by 2 was confirmed in cancer cells. Altogether, these results revealed an inhibition of LDH activity by ruthenium complex through a direct interaction structurally tuned by a Ru-C bond. %G English %2 https://inserm.hal.science/inserm-02365314/document %2 https://inserm.hal.science/inserm-02365314/file/1-s2.0-S016201341630215X-main.pdf %L inserm-02365314 %U https://inserm.hal.science/inserm-02365314 %~ INSERM %~ UNIV-STRASBG %~ FNCLCC %~ SITE-ALSACE