Facilitation of drug resistance development by gamma-irradiation in human cancer cells.

Hepatocellular carcinoma HepG2 cells (G cells) were subjected to selection first with gamma-radiation and then doxorubicin (Dox). The radiation treatment consisted of 2 Gy for 10 days (G2) or 10 Gy for 2 days (G10) and the Dox treatment was continuous exposure for up to 10 microM. Compared with respective parental G, G2, G10 cells, the Dox-selected cells showed mdr1 amplification/P-glycoprotein overexpression, Dox resistance and also less intracellular Dox accumulation. Verapamil reversed the drug resistance and increased the Dox accumulation in all cells. Decay in drug resistance and reduction in mdr1 amplification/P-glycoprotein overexpression were observed in the Dox-selected cells culturing in Dox-free condition. Among the Dox-selected cells, G2R cells showed the highest levels of drug resistance, mdr1 amplification, but the least resistance decay. Results from the study indicate the possible influence of radiation treatment on the development of drug resistance in cancer cells and it may even lead to a highly resistant phenotype.