title: Cytotoxicity of a mitochondriotropic quercetin derivative: mechanisms.
abstract: The mitochondriotropic compound 7-O-(4-triphenylphosphoniumbutyl)quercetin iodide (Q-7BTPI) in the μM concentration range caused necrotic death of cultured cells by acting as a prooxidant, with generation of superoxide anion in the mitochondria. Externally added membrane-permeating superoxide dismutase or catalase largely prevented death. Rescue by permeant catalase indicates that the toxicant is H(2)O(2), or reactive species derived from it. Rescue by permeant dismutase suggests the possibility of a chain mechanism of H(2)O(2) production, in which dismutation of superoxide constitutes a termination step. Oxidative stress was due to the presence of free phenolic hydroxyls and to accumulation in mitochondria, since the analogous mitochondriotropic per-O-methylated compound -3,3',4',5-tetra-O-methyl,7-O-(4-triphenylphosphoniumbutyl) quercetin iodide (QTM-7BTPI)-or Quercetin itself induced no or little superoxide production and cell death. Q-7BTPI did not cause a significant perturbation of the mitochondrial transmembrane potential or of respiration in cells. On the other hand its presence led to inhibition of glutathione peroxidase, an effect expected to accentuate oxidative stress by interfering with the elimination of H(2)O(2). An exogenous permeable glutathione precursor determined a strong increase of cellular glutathione levels but did not rescue the cells. Death induction was selective for fast-growing C-26 tumoral cells and mouse embryonic fibroblasts (MEFs) while sparing slow-growing MEFs. This suggests a possible use of Q-7BTPI as a chemotherapeutic agent.
authors.affiliation: Department of Biomedical Sciences, University of Padova, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Sassi
authors.forename: Lucia
authors.initials: L
authors.lastname: Biasutto
authors.forename: Andrea
authors.initials: A
authors.lastname: Mattarei
authors.forename: Massimo
authors.initials: M
authors.lastname: Carraro
authors.forename: Valentina
authors.initials: V
authors.lastname: Giorgio
authors.forename: Anna
authors.initials: A
authors.lastname: Citta
authors.forename: Paolo
authors.initials: P
authors.lastname: Bernardi
authors.forename: Spiridione
authors.initials: S
authors.lastname: Garbisa
authors.forename: Ildikò
authors.initials: I
authors.lastname: Szabò
authors.forename: Cristina
authors.initials: C
authors.lastname: Paradisi
authors.forename: Mario
authors.initials: M
authors.lastname: Zoratti
mesh_terms: D000818:Animals; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D019169:Jurkat Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D011794:Quercetin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D013481:Superoxides; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D011794:Quercetin; D006861:Hydrogen Peroxide; D005978:Glutathione