title: Overcoming multidrug resistance by targeting mitochondria with NO-donating doxorubicins.
abstract: A library of nitric oxide-donor doxorubicins (NO-DOXOs) was synthesized by linking appropriate NO-donor moieties at C-14 position through an ester bridge. Their hydrolytic stability was evaluated. The intracellular accumulation and cytotoxicity of these novel NO-DOXOs were studied in DOXO-sensitive (HT29) and DOXO-resistant (HT29/dx) tumor-cells. Hydrolytically-stable compounds accumulated in HT29 and HT29/dx cells, thanks to the nitration of plasma-membrane efflux transporters. Surprisingly, no close correlation was found between intracellular accumulation and cytotoxicity. Only compounds with high mitochondria retention (due to nitration of mitochondrial efflux transporter) exert high cytotoxicity, through the activation of a mitochondrial-dependent apoptosis.
authors.affiliation: Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Gazzano
authors.affiliation: Department of Science and Drug Technology, University of Torino, via Pietro Giuria 9, 10125 Torino, Italy.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Chegaev
authors.affiliation: Department of Science and Drug Technology, University of Torino, via Pietro Giuria 9, 10125 Torino, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Rolando
authors.affiliation: Department of Science and Drug Technology, University of Torino, via Pietro Giuria 9, 10125 Torino, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Blangetti
authors.affiliation: Department of Science and Drug Technology, University of Torino, via Pietro Giuria 9, 10125 Torino, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Annaratone
authors.affiliation: Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Ghigo
authors.affiliation: Department of Science and Drug Technology, University of Torino, via Pietro Giuria 9, 10125 Torino, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Fruttero
authors.affiliation: Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy. Electronic address: chiara.riganti@unito.it.
authors.forename: Chiara
authors.initials: C
authors.lastname: Riganti
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D019073:HT29 Cells; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020030:Nitric Oxide Donors / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D018528:ATP-Binding Cassette Transporters; D020030:Nitric Oxide Donors; D004317:Doxorubicin; D020169:Caspases
keywords: Doxorubicin; Mitochondria; Multidrug resistance; Nitric oxide