Potentiation of chemosensitivity in multidrug-resistant human leukemia CEM cells by inhibition of DNA-dependent protein kinase using wortmannin

다국어 초록 (Multilingual Abstract)

DNA-dependent protein kinase (DNA-PK) is activated by DNA stand breaks and participates in DNA repair. Its regulatory subunit, Ku autoantigen, binds to DNA and recruits the catalytic subunit (DNA-PKcs). We show here a new role of DNA-PK in the development of multidrug resistance (MDR). The Ku-DNA binding activity, the levels of Ku70/Ku80 and DNA-PKcs in MDR variants, CEM/VLB_(10-2). CEM/VLB_(55-8) and CEM/VLB_100 were higher than those in their parental drug-sensitive CEM cells in a drug resistance-dependent fashion. Also, CEM/VLB_100 cells showed about 3-fold increase of DNA-PK enzyme activity as compared with CEM cells. Similar results were observed in another MDR cell line, FM3A/M mouse mammary carcinoma cells. Moreover, we observed the CEM/VLB_100 cells were about 11-fold sensitive to wortmannin, which inhibits DNA-PK, compared with the CEM cells, and sensitized the MDR cells when combined with either bleomycin or vincristine, but have a little effect on CEM cells. Wortmannin was shown to inhibit DNA-PK and Ku-DNA binding activity of CEM/VLB_100 cells dose dependently but had a little or no effect on their parental cells. Our results suggested that enhanced expression of DNA-PK participates in the development of MDR, and the use of DNA-PK inhibitors such as wortmannin is likely to improve the effectiveness of anticancer drugs and thus could partially overcome drug resistance in DMR cells, through its ability to inhibit Ku/DNA-PK activity. ⓒ 2000 Elsevier Science Ltd. All rights reserved.