title: Impact of cyclometalated ruthenium(II) complexes on lactate dehydrogenase activity and cytotoxicity in gastric and colon cancer cells.
abstract: 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 Kior i0.5values 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 LDHrmwere 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.
authors: Instituto de Química UNAM, Circuito Exterior s/n, Ciudad Universitaria, 04510 México D.F., Mexico.
authors: Hugo
authors: H
authors: Rico Bautista
authors: Instituto de Química UNAM, Circuito Exterior s/n, Ciudad Universitaria, 04510 México D.F., Mexico.
authors: Rafael Omar
authors: RO
authors: Saavedra Díaz
authors: Department of Chemistry, Carnegie Mellon University, 4400 Fifth Avenue, Pittsburgh, PA 15213, USA.
authors: Longzhu Q
authors: LQ
authors: Shen
authors: INSERM U1113, Strasbourg University, FMTS, 3 Avenue Molière, 67200 Strasbourg, France; Oncology Section, FMTS, Strasbourg University, Strasbourg, France.
authors: Christophe
authors: C
authors: Orvain
authors: INSERM U1113, Strasbourg University, FMTS, 3 Avenue Molière, 67200 Strasbourg, France; Oncology Section, FMTS, Strasbourg University, Strasbourg, France.
authors: Christian
authors: C
authors: Gaiddon
authors: Instituto de Química UNAM, Circuito Exterior s/n, Ciudad Universitaria, 04510 México D.F., Mexico. Electronic address: ronan@unam.mx.
authors: Ronan
authors: R
authors: Le Lagadec
authors: Department of Chemistry, Carnegie Mellon University, 4400 Fifth Avenue, Pittsburgh, PA 15213, USA.
authors: Alexander D
authors: AD
authors: Ryabov
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D003603:Cytotoxins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012428:Ruthenium / Q000737:chemistry / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D003603:Cytotoxins; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D012428:Ruthenium; D007770:L-Lactate Dehydrogenase
keywords: Cyclometalation; Cytotoxicity; Enzyme inhibition; Lactate dehydrogenase; Molecular docking; Ruthenium