title: Small structural changes on a hydroquinone scaffold determine the complex I inhibition or uncoupling of tumoral oxidative phosphorylation.
abstract: Mitochondria participate in several distinctiveness of cancer cell, being a promising target for the design of anti-cancer compounds. Previously, we described that ortho-carbonyl hydroquinone scaffold 14 inhibits the complex I-dependent respiration with selective anti-proliferative effect on mouse mammary adenocarcinoma TA3/Ha cancer cells; however, the structural requirements of this hydroquinone scaffold to affect the oxidative phosphorylation (OXPHOS) of cancer cells have not been studied in detail. Here, we characterize the mitochondrial metabolism of TA3/Ha cancer cells, which exhibit a high oxidative metabolism, and evaluate the effect of small structural changes of the hydroquinone scaffold 14 on the respiration of this cell line. Our results indicate that these structural changes modify the effect on OXPHOS, obtaining compounds with three alternative actions: inhibitors of complex I-dependent respiration, uncoupler of OXPHOS and compounds with both actions. To confirm this, the effect of a bicyclic hydroquinone (9) was evaluated in isolated mitochondria. Hydroquinone 9 increased mitochondrial respiration in state 4o without effects on the ADP-stimulated respiration (state 3ADP), decreasing the complexes I and II-dependent respiratory control ratio. The effect on mitochondrial respiration was reversed by 6-ketocholestanol addition, indicating that this hydroquinone is a protonophoric uncoupling agent. In intact TA3/Ha cells, hydroquinone 9 caused mitochondrial depolarization, decreasing intracellular ATP and NAD(P)H levels and GSH/GSSG ratio, and slightly increasing the ROS levels. Moreover, it exhibited selective NAD(P)H availability-dependent anti-proliferative effect on cancer cells. Therefore, our results indicate that the ortho-carbonyl hydroquinone scaffold offers the possibility to design compounds with specific actions on OXPHOS of cancer cells.
authors.affiliation: Programa de Farmacología Molecular y Clínica, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Independencia 1027, Casilla 7, Santiago, Chile. Electronic address: felix.urra@qf.uchile.cl.
authors.forename: Félix A
authors.initials: FA
authors.lastname: Urra
authors.affiliation: Departamento de Química Orgánica y Físico-Química, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Casilla 233, Santiago 1, Chile.
authors.forename: Miguel
authors.initials: M
authors.lastname: Córdova-Delgado
authors.affiliation: Programa de Farmacología Molecular y Clínica, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Independencia 1027, Casilla 7, Santiago, Chile.
authors.forename: Michel
authors.initials: M
authors.lastname: Lapier
authors.affiliation: Programa de Farmacología Molecular y Clínica, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Independencia 1027, Casilla 7, Santiago, Chile.
authors.forename: Andrea
authors.initials: A
authors.lastname: Orellana-Manzano
authors.affiliation: Departamento de Química Orgánica y Físico-Química, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Casilla 233, Santiago 1, Chile.
authors.forename: Luis
authors.initials: L
authors.lastname: Acevedo-Arévalo
authors.affiliation: Departamento de Química Orgánica y Físico-Química, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Casilla 233, Santiago 1, Chile.
authors.forename: Hernán
authors.initials: H
authors.lastname: Pessoa-Mahana
authors.affiliation: Departamento de Química Orgánica y Físico-Química, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Casilla 233, Santiago 1, Chile.
authors.forename: Jaime M
authors.initials: JM
authors.lastname: González-Vivanco
authors.affiliation: Instituto de Química de Recursos Naturales, Universidad de Talca, Casilla 747, Talca, Chile.
authors.forename: Maximiliano
authors.initials: M
authors.lastname: Martínez-Cifuentes
authors.affiliation: Departamento de Química Orgánica y Físico-Química, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Casilla 233, Santiago 1, Chile.
authors.forename: Oney
authors.initials: O
authors.lastname: Ramírez-Rodríguez
authors.affiliation: Departamento de Química Orgánica y Físico-Química, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Casilla 233, Santiago 1, Chile.
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Millas-Vargas
authors.affiliation: Departamento de Química, Facultad de Ciencias, Universidad de Chile, Casilla 653, Santiago, Chile.
authors.forename: Boris
authors.initials: B
authors.lastname: Weiss-López
authors.affiliation: Programa de Farmacología Molecular y Clínica, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Independencia 1027, Casilla 7, Santiago, Chile.
authors.forename: Mario
authors.initials: M
authors.lastname: Pavani
authors.affiliation: Programa de Farmacología Molecular y Clínica, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Independencia 1027, Casilla 7, Santiago, Chile. Electronic address: jferreir@med.uchile.cl.
authors.forename: Jorge
authors.initials: J
authors.lastname: Ferreira
authors.affiliation: Instituto de Química de Recursos Naturales, Universidad de Talca, Casilla 747, Talca, Chile. Electronic address: raraya@utalca.cl.
authors.forename: Ramiro
authors.initials: R
authors.lastname: Araya-Maturana
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D006873:Hydroquinones / Q000737:chemistry* / Q000633:toxicity*; D008297:Male; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D051381:Rats; D014475:Uncoupling Agents / Q000737:chemistry* / Q000633:toxicity*
chemical_list: D006873:Hydroquinones; D014475:Uncoupling Agents; D042967:Electron Transport Complex I; C031927:hydroquinone
keywords: Anti-cancer agents; Complex I; Hydroquinones; Oxidative phosphorylation; Uncouplers