title: Mitochondria-targeted resveratrol derivatives act as cytotoxic pro-oxidants.
abstract: Resveratrol derivatives bearing an O-linked mitochondria-targeting 4-triphenylphosphoniumbutyl group at either position 3 or position 4' are prooxidant and cytotoxic for cultured cells, selectively killing fast-growing cells when supplied in the low μM range. Resveratrol is essentially without effect under these experimental conditions, while the cytotoxicity of the mitochondriotropic derivatives increases if they are methylated on the remaining hydroxyls. Experiments with Bax(-/-)/Bak(-/-) cells and a pan-caspase inhibitor show that cell death is mostly of the necrotic type. Cytotoxicity is due to ROS produced upon accumulation of the compounds into mitochondria, and specifically to H2O2, since externally added membrane-permeant catalase largely prevents cell death while superoxide dismutase potentiates toxicity. The mitochondriotropic compounds cause ROS-independent depolarization of in situ mitochondria. Effectiveness is increased if resveratrol hydroxyls are acetylated or methylated; this excludes the involvement of autooxidation of the polyphenolic nucleus and a protonophoric cycle as the causes of ROS generation and of depolarization, respectively. Resveratrol-triphenylphosphonium conjugates may thus represent a new class of chemotherapeutic agents, redox-active "mitocans", whose mechanisms of action and in vivo activity are worthy of further investigation.
authors.forename: Nicola
authors.initials: N
authors.lastname: Sassi
authors.forename: Andrea
authors.initials: A
authors.lastname: Mattarei
authors.forename: Michele
authors.initials: M
authors.lastname: Azzolini
authors.forename: Paolo
authors.initials: P
authors.lastname: Bernardi
authors.forename: Ildiko'
authors.initials: I
authors.lastname: Szabo'
authors.forename: Cristina
authors.initials: C
authors.lastname: Paradisi
authors.forename: Mario
authors.initials: M
authors.lastname: Zoratti
authors.affiliation: CNR Institute of Neuroscience, c/o Dept. of Biomedical Sciences, Viale Giuseppe Colombo 3, 35121 Padova, Italy. lucia.biasutto@unipd.it.
authors.forename: Lucia
authors.initials: L
authors.lastname: Biasutto
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D055786:Gene Knockout Techniques; D006861:Hydrogen Peroxide / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009336:Necrosis / Q000473:pathology; D016877:Oxidants / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000077185:Resveratrol; D013267:Stilbenes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000235:genetics
chemical_list: D016877:Oxidants; D017382:Reactive Oxygen Species; D013267:Stilbenes; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D006861:Hydrogen Peroxide; D000077185:Resveratrol