title: Destabilization of mitochondrial functions as a target against breast cancer progression: Role of TPP(+)-linked-polyhydroxybenzoates.
abstract: Mitochondrion is an accepted molecular target in cancer treatment since it exhibits a higher transmembrane potential in cancer cells, making it susceptible to be targeted by lipophilic-delocalized cations of triphenylphosphonium (TPP(+)). Thus, we evaluated five TPP(+)-linked decyl polyhydroxybenzoates as potential cytotoxic agents in several human breast cancer cell lines that differ in estrogen receptor and HER2/neu expression, and in metabolic profile. Results showed that all cell lines tested were sensitive to the cytotoxic action of these compounds. The mechanism underlying the cytotoxicity would be triggered by their weak uncoupling effect on the oxidative phosphorylation system, while having a wider and safer therapeutic range than other uncouplers and a significant lowering in transmembrane potential. Noteworthy, while the TPP(+)-derivatives alone led to almost negligible losses of ATP, when these were added in the presence of an AMP-activated protein kinase inhibitor, the levels of ATP fell greatly. Overall, data presented suggest that decyl polyhydroxybenzoates-TPP(+) and its derivatives warrant future investigation as potential anti-tumor agents.
authors.affiliation: Clinical and Molecular Pharmacology Program, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Av. Independencia 1027, Santiago 8380453, Chile; Laboratory of Antioxidants, Nutrition and Food Technology Institute, University of Chile, El Líbano 5524, Santiago 7830490, Chile.
authors.forename: Cristian
authors.initials: C
authors.lastname: Sandoval-Acuña
authors.affiliation: Clinical and Molecular Pharmacology Program, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Av. Independencia 1027, Santiago 8380453, Chile.
authors.forename: Sebastián
authors.initials: S
authors.lastname: Fuentes-Retamal
authors.affiliation: Clinical and Molecular Pharmacology Program, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Av. Independencia 1027, Santiago 8380453, Chile.
authors.forename: Daniela
authors.initials: D
authors.lastname: Guzmán-Rivera
authors.affiliation: Clinical and Molecular Pharmacology Program, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Av. Independencia 1027, Santiago 8380453, Chile.
authors.forename: Liliana
authors.initials: L
authors.lastname: Peredo-Silva
authors.affiliation: Department of Chemistry, Faculty of Basic Sciences, Metropolitan Educational Sciences University, Av. José Pedro Alessandri 774, Santiago 7760197, Chile.
authors.forename: Matías
authors.initials: M
authors.lastname: Madrid-Rojas
authors.affiliation: Department of Chemistry, Faculty of Basic Sciences, Metropolitan Educational Sciences University, Av. José Pedro Alessandri 774, Santiago 7760197, Chile.
authors.forename: Solange
authors.initials: S
authors.lastname: Rebolledo
authors.affiliation: Department of Organic and Physical Chemistry, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santos Dumont 964, Santiago 8380494, Chile.
authors.forename: Vicente
authors.initials: V
authors.lastname: Castro-Castillo
authors.affiliation: Clinical and Molecular Pharmacology Program, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Av. Independencia 1027, Santiago 8380453, Chile.
authors.forename: Mario
authors.initials: M
authors.lastname: Pavani
authors.affiliation: Clinical and Molecular Pharmacology Program, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Av. Independencia 1027, Santiago 8380453, Chile.
authors.forename: Mabel
authors.initials: M
authors.lastname: Catalán
authors.affiliation: Clinical and Molecular Pharmacology Program, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Av. Independencia 1027, Santiago 8380453, Chile.
authors.forename: Juan Diego
authors.initials: JD
authors.lastname: Maya
authors.affiliation: Unit of Pharmacology and Pharmacogenetics, Institute of Dental Sciences Research (ICOD), Faculty of Dentistry, University of Chile, Sergio Livingstone Polhammer 94, Santiago 8380492, Chile.
authors.forename: José A
authors.initials: JA
authors.lastname: Jara
authors.affiliation: School of Medicine, Faculty of Health Sciences, University of Tarapacá, Av. General Velásquez 1775, Arica 1000007, Chile.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Parra
authors.affiliation: Institute for Advanced Research, University of Tarapacá, Antofagasta 1520, Arica 1001236, Chile.
authors.forename: Gloria M
authors.initials: GM
authors.lastname: Calaf
authors.affiliation: Laboratory of Antioxidants, Nutrition and Food Technology Institute, University of Chile, El Líbano 5524, Santiago 7830490, Chile.
authors.forename: Hernán
authors.initials: H
authors.lastname: Speisky
authors.affiliation: Clinical and Molecular Pharmacology Program, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Av. Independencia 1027, Santiago 8380453, Chile. Electronic address: jferreir@med.uchile.cl.
authors.forename: Jorge
authors.initials: J
authors.lastname: Ferreira
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D018450:Disease Progression; D005260:Female; D006801:Humans; D062385:Hydroxybenzoates / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D009943:Organophosphorus Compounds / Q000737:chemistry*; D010100:Oxygen / Q000378:metabolism
chemical_list: D062385:Hydroxybenzoates; D009943:Organophosphorus Compounds; D000255:Adenosine Triphosphate; D010100:Oxygen
keywords: Human breast cancer; Mitochondrially-targeted decyl polyhydroxybenzoates; Transmembrane potential; Triphenylphosphonium-derivatives; Weak uncoupling of the oxidative phosphorylation system