title: Mitochondrial-targeting nitrooxy-doxorubicin: a new approach to overcome drug resistance.
abstract: In previous studies, we showed that nitric oxide (NO) donors and synthetic doxorubicins (DOXs) modified with moieties containing NO-releasing groups--such as nitrooxy-DOX (NitDOX) or 3-phenylsulfonylfuroxan-DOX (FurDOX)--overcome drug resistance by decreasing the activity of ATP-binding cassette (ABC) transporters that can extrude the drug. Here, we have investigated the biochemical mechanisms by which NitDOX and FurDOX exert antitumor effects. Both NitDOX and FurDOX were more cytotoxic than DOX against drug-resistant cells. Interestingly, NitDOX exhibited a faster uptake and an extranuclear distribution. NitDOX was preferentially localized in the mitochondria, where it nitrated and inhibited the mitochondria-associated ABC transporters, decreased the flux through the tricarboxylic acid cycle, slowed down the activity of complex I, lowered the synthesis of ATP, induced oxidative and nitrosative stress, and elicited the release of cytochrome c and the activation of caspase-9 and -3 in DOX-resistant cells. We suggest that NitDOX may represent the prototype of a new class of multifunctional anthracyclines, which have cellular targets different from conventional anthracyclines and greater efficacy against drug-resistant tumors.
authors.affiliation: Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Riganti
authors.forename: Barbara
authors.initials: B
authors.lastname: Rolando
authors.forename: Joanna
authors.initials: J
authors.lastname: Kopecka
authors.forename: Ivana
authors.initials: I
authors.lastname: Campia
authors.forename: Konstantin
authors.initials: K
authors.lastname: Chegaev
authors.forename: Loretta
authors.initials: L
authors.lastname: Lazzarato
authors.forename: Antonella
authors.initials: A
authors.lastname: Federico
authors.forename: Roberta
authors.initials: R
authors.lastname: Fruttero
authors.forename: Dario
authors.initials: D
authors.lastname: Ghigo
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002952:Citric Acid Cycle / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D042967:Electron Transport Complex I / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D020014:K562 Cells; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects
chemical_list: D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D020030:Nitric Oxide Donors; D009569:Nitric Oxide; D004317:Doxorubicin; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D053148:Caspase 3; D053453:Caspase 9; D004250:DNA Topoisomerases, Type II; D042967:Electron Transport Complex I