title: Liposomal nitrooxy-doxorubicin: one step over caelyx in drug-resistant human cancer cells.
abstract: In this work we prepared and characterized two liposomal formulations of a semisynthetic nitric oxide (NO)-releasing doxorubicin (Dox), called nitrooxy-Dox (NitDox), which we previously demonstrated to be cytotoxic in Dox-resistant human colon cancer cells. Liposomes with 38.2% (Lip A) and 19.1% (Lip B) cholesterol were synthesized: both formulations had similar size and zeta potential values and caused the same intracellular distribution of free NitDox, but Lip B accumulated and released NitDox more efficiently. In Dox-resistant human colon cancer cells, Lip A and Lip B exhibited a more favorable kinetics of drug uptake and NO release, and a stronger cytotoxicity than Dox and free NitDox. While Caelyx, one of the liposomal Dox formulations approved for breast and ovary tumors treatment, was ineffective in Dox-resistant breast/ovary cancer cells, Lip B, and to a lesser extent Lip A, still exerted a significant cytotoxicity in these cells. This event was accompanied in parallel by a higher release of NO, which caused nitration of P-glycoprotein (Pgp) and multidrug resistance related protein 1 (MRP1), two transporters involved in Dox efflux, and impaired their pump activity. By doing so, the efflux kinetics of Dox after treatment with Lip B was markedly slowed down and the intracellular accumulation of Dox was increased in breast and ovary drug-resistant cells. We propose these liposomal formulations of NitDox as new tools with a specific indication for tumors overexpressing Pgp and MRP1.
authors: Department of Drug Science and Technology, University of Torino , via Pietro Giuria 9, 10125 Torino, Italy.
authors: Isabella
authors: I
authors: Pedrini
authors: Elena
authors: E
authors: Gazzano
authors: Konstantin
authors: K
authors: Chegaev
authors: Barbara
authors: B
authors: Rolando
authors: Alessandro
authors: A
authors: Marengo
authors: Joanna
authors: J
authors: Kopecka
authors: Roberta
authors: R
authors: Fruttero
authors: Dario
authors: D
authors: Ghigo
authors: Silvia
authors: S
authors: Arpicco
authors: Chiara
authors: C
authors: Riganti
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D019073:HT29 Cells; D006801:Humans; D007700:Kinetics; D008081:Liposomes / Q000737:chemistry* / Q000494:pharmacology; D061986:MCF-7 Cells; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009569:Nitric Oxide / Q000737:chemistry; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D004317:Doxorubicin; D004337:Drug Carriers; D008081:Liposomes; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009569:Nitric Oxide; D011092:Polyethylene Glycols; C506643:liposomal doxorubicin; C421109:multidrug resistance-associated protein 1