title: Casiopeina II-gly and bromo-pyruvate inhibition of tumor hexokinase, glycolysis, and oxidative phosphorylation.
abstract: The copper-based drug Casiopeina II-gly (CasII-gly) shows potent antineoplastic effect and diminishes mitochondrial metabolism on several human and rodent malignant tumors. To elucidate whether CasII-gly also affects glycolysis, (a) the flux through the complete pathway and the initial segment and (b) the activities of several glycolytic enzymes of AS-30D hepatocarcinoma cells were determined. CasII-gly (IC₅₀ = 0.74-6.7 μM) was more effective to inhibit 24-72 h growth of several human carcinomas than 3-bromopyruvate (3BrPyr) (IC₅₀ = 45-100 μM) with no apparent effect on normal human-proliferating lymphocytes and HUVECs. In short-term 60-min experiments, CasII-gly increased tumor cell lactate production and glycogen breakdown. CasII-gly was 1.3-21 times more potent than 3BrPyr and cisplatin to inhibit tumor HK. As CasII-gly inhibited the soluble and mitochondrial HK activities and the flux through the HK-TPI glycolytic segment, whereas PFK-1, GAPDH, PGK, PYK activities and HPI-TPI segment flux were not affected, the data suggested glycogenolysis activation induced by HK inhibition. Accordingly, glycogen-depleted as well as oligomycin-treated cancer cells became more sensitive to CasII-gly. The inhibition time-course of HK by CasII-gly was slower than that of OxPhos in AS-30D cells, indicating that glycolytic toxicity was secondary to mitochondria, the primary CasII-gly target. In long-term 24-h experiments with HeLa cells, 5 μM CasII-gly inhibited OxPhos (80%), glycolysis (40%), and HK (42%). The present data indicated that CasII-gly is an effective multisite anticancer drug simultaneously targeting mitochondria and glycolysis.
authors.affiliation: Departamento de Bioquímica, Instituto Nacional de Cardiología, Juan Badiano No. 1, Col. Sección XVI Tlalpan, 14080 Mexico, DF, Mexico. marinhernndez@yahoo.com.mx
authors.forename: Alvaro
authors.initials: A
authors.lastname: Marín-Hernández
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Gallardo-Pérez
authors.forename: Sayra Y
authors.initials: SY
authors.lastname: López-Ramírez
authors.forename: Jorge Donato
authors.initials: JD
authors.lastname: García-García
authors.forename: José Salud
authors.initials: JS
authors.lastname: Rodríguez-Zavala
authors.forename: Lena
authors.initials: L
authors.lastname: Ruiz-Ramírez
authors.forename: Isabel
authors.initials: I
authors.lastname: Gracia-Mora
authors.forename: Alejandro
authors.initials: A
authors.lastname: Zentella-Dehesa
authors.forename: Marcela
authors.initials: M
authors.lastname: Sosa-Garrocho
authors.forename: Marina
authors.initials: M
authors.lastname: Macías-Silva
authors.forename: Rafael
authors.initials: R
authors.lastname: Moreno-Sánchez
authors.forename: Sara
authors.initials: S
authors.lastname: Rodríguez-Enríquez
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004734:Energy Metabolism / Q000187:drug effects; D006003:Glycogen / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects*; D006593:Hexokinase / Q000378:metabolism*; D006801:Humans; D007773:Lactates / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects; D009942:Organometallic Compounds / Q000494:pharmacology*; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D010732:Phosphofructokinase-1 / Q000378:metabolism; D011770:Pyruvate Kinase / Q000378:metabolism; D011773:Pyruvates / Q000494:pharmacology*; D051381:Rats
chemical_list: D000970:Antineoplastic Agents; D007773:Lactates; D009942:Organometallic Compounds; D011773:Pyruvates; C505569:casiopeina II-glycine; C017092:bromopyruvate; D006003:Glycogen; D006593:Hexokinase; D010732:Phosphofructokinase-1; D011770:Pyruvate Kinase