Ryu, J. S., Um, J. H., Kang, C. D., Bae, J. H., Kim, D. U., Lee, Y. J., Kim, D. W., Chung, B. S. and Kim, S. H. 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. Radiat. Res. 162, 527–535 (2004).
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-κB, EGFR, MDM2 and Ku70/80, and the suppression of HIF-1α 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.