title: The nitroxide Tempol modulates anthracycline resistance in breast cancer cells.
abstract: The occurrence of multidrug resistance (MDR) is the major obstacle to successful anthracycline-based cancer chemotherapy. In the present study, we assessed the effects of Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl, TPL), a piperidine nitroxide with growth-inhibitory properties in tumor cell lines, on a number of molecular mechanisms involved in the resistance of human breast adenocarcinoma cell lines to doxorubicin (DOX). Cytotoxicity studies in MCF-7 wildtype and their MDR variant MCF-7 Adr(R) cells showed a synergistic effect between TPL and DOX when exposure to TPL preceded or was simultaneous with DOX treatment in MCF-7 Adr(R) cells. This effect of TPL seems to be due in part to its ability to increase peroxide levels and to deplete cellular glutathione pools. In addition, TPL increased DOX accumulation in MCF-7 Adr(R) cells by interfering with P-glycoprotein-mediated DOX efflux, as evidenced using a specific antibody that recognizes the active form of the protein. TPL was also found to affect the expression levels of proteins involved in response to drug treatment (e.g., p53, bcl2, bax, p21). Taken together, our results indicate that TPL is a potential new agent that may improve the clinical effect of DOX in tumors exhibiting a MDR phenotype.
authors.affiliation: DBSF, University of Insubria, Busto Arsizio, Varese, Italy.
authors.forename: Marzia B
authors.initials: MB
authors.lastname: Gariboldi
authors.forename: Francesca
authors.initials: F
authors.lastname: Terni
authors.forename: Raffaella
authors.initials: R
authors.lastname: Ravizza
authors.forename: Stefania
authors.initials: S
authors.lastname: Meschini
authors.forename: Manuela
authors.initials: M
authors.lastname: Marra
authors.forename: Maria
authors.initials: M
authors.lastname: Condello
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Arancia
authors.forename: Elena
authors.initials: E
authors.lastname: Monti
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D018384:Oxidative Stress; D013113:Spin Labels
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003497:Cyclic N-Oxides; D013113:Spin Labels; D004317:Doxorubicin; D005978:Glutathione; C001803:tempol