title: Synthesis and biological evaluation of a series of flavone derivatives as potential radioligands for imaging the multidrug resistance-associated protein 1 (ABCC1/MRP1).
abstract: Multidrug resistance (MDR) is one of the major problems affecting the treatment of cancer. In vivo visualization and quantification of MDR proteins would be of great value to better select the therapeutic strategy. Six flavone-based compounds were synthesized and evaluated for their cytotoxic activity and MDR-reversing capacity using hMRP1 or hMDR1 overexpressing cell lines for in vitro assays. All the flavone derivatives were highly selective for hMRP1-expressing cell lines. These derivatives each used at 4muM (a non-cytotoxic concentration) enhance significantly the sensitivity of hMRP1-mediated MDR cell line toward doxorubicin toxicity. Their MDR-reversing capacity suggests that, in particular, the 4'-fluoroalkyloxy and 4'-iodo apigenin derivatives are potential new radiopharmaceuticals to visualize in vivo MRP1-mediated MDR phenomenon by PET or SPECT.
authors.affiliation: Université François Rabelais, Faculté de Pharmacie, Lab. de Biophysique Médicale et Pharmaceutique, INSERM U619, Tours, France. sylvie.mavel@univ-tours.fr
authors.forename: Sylvie
authors.initials: S
authors.lastname: Mavel
authors.forename: Branko
authors.initials: B
authors.lastname: Dikic
authors.forename: Somchit
authors.initials: S
authors.lastname: Palakas
authors.forename: Patrick
authors.initials: P
authors.lastname: Emond
authors.forename: Ivan
authors.initials: I
authors.lastname: Greguric
authors.forename: Adrienne Gomez
authors.initials: AG
authors.lastname: de Gracia
authors.forename: Filomena
authors.initials: F
authors.lastname: Mattner
authors.forename: Manuel
authors.initials: M
authors.lastname: Garrigos
authors.forename: Denis
authors.initials: D
authors.lastname: Guilloteau
authors.forename: Andrew
authors.initials: A
authors.lastname: Katsifis
mesh_terms: D047310:Apigenin / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000633:toxicity; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D047309:Flavones / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D008956:Models, Chemical; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D047310:Apigenin; D004317:Doxorubicin; D047309:Flavones; D008024:Ligands; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D019275:Radiopharmaceuticals; C421109:multidrug resistance-associated protein 1