title: Development of chromanes as novel inhibitors of the uncoupling proteins.
abstract: The uncoupling proteins (UCPs) are mitochondrial carriers that modulate the energetic efficiency and, as a result, can lower superoxide levels. Here, we describe the discovery of a small-molecule inhibitor of the UCPs. Screening of potential UCP1 regulators led to the identification of chromane derivatives that inhibit its proton conductance. Members of the UCP family can act as a defense against oxidative stress and, thus, UCP2 plays a protective role in tumor cells. High UCP2 levels have been associated with chemoresistance. We demonstrate that chromanes also inhibit UCP2 and, in HT-29 human carcinoma cells, cause oxidative stress. The chromane derivatives can act synergistically with chemotherapeutic agents; for instance, they increase the toxicity of arsenic trioxide in HT-29 cells. These findings open a promising line in the development of novel anticancer agents.
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Cientificas, Madrid, Spain. rial@cib.csic.es
authors.forename: Eduardo
authors.initials: E
authors.lastname: Rial
authors.forename: Leonor
authors.initials: L
authors.lastname: Rodríguez-Sánchez
authors.forename: Patricio
authors.initials: P
authors.lastname: Aller
authors.forename: Arancha
authors.initials: A
authors.lastname: Guisado
authors.forename: M
authors.initials: M
authors.lastname: Mar González-Barroso
authors.forename: Eunate
authors.initials: E
authors.lastname: Gallardo-Vara
authors.forename: Mariano
authors.initials: M
authors.lastname: Redondo-Horcajo
authors.forename: Esther
authors.initials: E
authors.lastname: Castellanos
authors.forename: Roberto
authors.initials: R
authors.lastname: Fernández de la Pradilla
authors.forename: Alma
authors.initials: A
authors.lastname: Viso
mesh_terms: D000818:Animals; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002839:Chromans / Q000737:chemistry / Q000494:pharmacology*; D055808:Drug Discovery; D004357:Drug Synergism; D005227:Fatty Acids / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D007473:Ion Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000166:cytology; D051379:Mice; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010087:Oxides / Q000494:pharmacology; D011522:Protons; D051381:Rats; D012441:Saccharomyces cerevisiae / Q000235:genetics; D013481:Superoxides / Q000378:metabolism; D000071256:Uncoupling Protein 1; D000071246:Uncoupling Protein 2
chemical_list: D001152:Arsenicals; D002839:Chromans; D005227:Fatty Acids; D007473:Ion Channels; D024101:Mitochondrial Proteins; D010087:Oxides; D011522:Protons; C000604371:UCP1 protein, human; C000604389:UCP2 protein, human; C000604372:Ucp1 protein, mouse; C000604373:Ucp1 protein, rat; C000604390:Ucp2 protein, mouse; C000604391:Ucp2 protein, rat; D000071256:Uncoupling Protein 1; D000071246:Uncoupling Protein 2; D013481:Superoxides; D000077237:Arsenic Trioxide