title: Fractionated irradiation leads to restoration of drug sensitivity in MDR cells that correlates with down-regulation of P-gp and DNA-dependent protein kinase activity.
abstract: We showed that the drug sensitivity of multidrug-resistant (MDR) cells could be enhanced by fractionated irradiation. The molecular changes associated with fractionated radiation-induced chemosensitization were characterized. Irradiated cells of the multidrug-resistant CEM/MDR sublines (CEM/MDR/IR1, 2 and 3) showed a loss of P-glycoprotein (P-gp) and concurrent reduction of Ku DNA binding and DNA-PK activities with decreased level of Ku70/80 and increased level of DNA-PKcs, and these changes were followed by an increased susceptibility to anticancer drugs. These irradiated MDR cells also exhibited the reduction of other chemoresistance-related proteins, including BCL2, NF-kappaB, EGFR, MDM2 and Ku70/80, and the suppression of HIF-1alpha expression induced by hypoxia. In contrast, fractionated irradiation increased the levels of these proteins and induced drug resistance in the parental drug-sensitive CEM cells. These results suggest that the chemoresistance-related proteins are differentially modulated in drug-sensitive and MDR cells by fractionated irradiation, and the optimized treatment with fractionated radiation could lead to new chemoradiotherapeutic strategies to treat multidrug-resistant tumors.
authors.affiliation: Department of Biochemistry, College of Medicine, Pusan National University, Pusan 602-739, South Korea.
authors.forename: Jun Sun
authors.initials: JS
authors.lastname: Ryu
authors.forename: Jee Hyun
authors.initials: JH
authors.lastname: Um
authors.forename: Chi Dug
authors.initials: CD
authors.lastname: Kang
authors.forename: Jae Ho
authors.initials: JH
authors.lastname: Bae
authors.forename: Doo Un
authors.initials: DU
authors.lastname: Kim
authors.forename: Yun Jung
authors.initials: YJ
authors.lastname: Lee
authors.forename: Dong Wan
authors.initials: DW
authors.lastname: Kim
authors.forename: Byung Seon
authors.initials: BS
authors.lastname: Chung
authors.forename: Sun Hee
authors.initials: SH
authors.lastname: Kim
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004265:DNA Helicases / Q000096:biosynthesis; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D019583:Dose Fractionation, Radiation; D004307:Dose-Response Relationship, Radiation; D015536:Down-Regulation; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D000860:Hypoxia; D020128:Inhibitory Concentration 50; D000072200:Ku Autoantigen; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009369:Neoplasms / Q000532:radiotherapy*; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis*; D011874:Radiometry
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004265:DNA Helicases; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D000072200:Ku Autoantigen; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; C497263:PRKDC protein, human; C106893:XRCC5 protein, human