title: Anticancer activity of structurally related ruthenium(II) cyclopentadienyl complexes.
abstract: A set of structurally related Ru(η(5)-C5H5) complexes with bidentate N,N'-heteroaromatic ligands have been evaluated as prospective metallodrugs, with focus on exploring the uptake and cell death mechanisms and potential cellular targets. We have extended these studies to examine the potential of these complexes to target cancer cell metabolism, the energetic-related phenotype of cancer cells. The observations that these complexes can enter cells, probably facilitated by binding to plasma transferrin, and can be retained preferentially at the membranes prompted us to explore possible membrane targets involved in cancer cell metabolism. Most malignant tumors present the Warburg effect, which consists in increasing glycolytic rates with production of lactate, even in the presence of oxygen. The reliance of glycolytic cancer cells on trans-plasma-membrane electron transport (TPMET) systems for their continued survival raises the question of their appropriateness as a target for anticancer drug development strategies. Considering the interesting findings that some anticancer drugs in clinical use are cytotoxic even without entering cells and can inhibit TPMET activity, we investigated whether redox enzyme modulation could be a potential mechanism of action of antitumor ruthenium complexes. The results from this study indicated that ruthenium complexes can inhibit lactate production and TPMET activity in a way dependent on the cancer cell aggressiveness and the concentration of the complex. Combination approaches that target cell metabolism (glycolytic inhibitors) as well as proliferation are needed to successfully cure cancer. This study supports the potential use of some of these ruthenium complexes as adjuvants of glycolytic inhibitors in the treatment of aggressive cancers.
authors.affiliation: Unidade Ciências Químicas e Radiofarmacêuticas, Instituto Superior Técnico, Universidade de Lisboa, Polo de Loures-Campus Tecnológico e Nuclear, Estrada Nacional 10, km 139.7, 2695-066, Bobadela LRS Sacavém, Portugal.
authors.forename: Leonor
authors.initials: L
authors.lastname: Côrte-Real
authors.forename: Filipa
authors.initials: F
authors.lastname: Mendes
authors.forename: Joana
authors.initials: J
authors.lastname: Coimbra
authors.forename: Tânia S
authors.initials: TS
authors.lastname: Morais
authors.forename: Ana Isabel
authors.initials: AI
authors.lastname: Tomaz
authors.forename: Andreia
authors.initials: A
authors.lastname: Valente
authors.forename: M Helena
authors.initials: MH
authors.lastname: Garcia
authors.forename: Isabel
authors.initials: I
authors.lastname: Santos
authors.forename: Manuel
authors.initials: M
authors.lastname: Bicho
authors.forename: Fernanda
authors.initials: F
authors.lastname: Marques
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003517:Cyclopentanes / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D061986:MCF-7 Cells; D008968:Molecular Conformation; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012428:Ruthenium / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D003517:Cyclopentanes; D009942:Organometallic Compounds; D012428:Ruthenium