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.
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.
Ryu
Jun Sun
JS
Department of Biochemistry, College of Medicine, Pusan National University, Pusan 602-739, South Korea.
Um
Jee Hyun
JH
Kang
Chi Dug
CD
Bae
Jae Ho
JH
Kim
Doo Un
DU
Lee
Yun Jung
YJ
Kim
Dong Wan
DW
Chung
Byung Seon
BS
Kim
Sun Hee
SH
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
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