7-Hydroxystaurosporine (UCN-01) preferentially sensitizes cells with a disrupted TP53 to gamma radiation in lung cancer cell lines.
Mutations in TP53 occur in more than 50% of the lung cancer patients and are associated with an increased resistance to chemotherapy and radiotherapy. The human lung adenocarcinoma cell lines A549 and LXSN contain a wild-type TP53 and were growth arrested at both the G(1)- and G(2)-phase checkpoints after irradiation. However, a TP53-disrupted cell line, E6, was arrested only at the G(2)-phase checkpoint. UCN-01 (7-hydroxystaurosporine), a CHEK1 inhibitor that abrogates the G(2) block, has been reported to enhance radiation toxicity in human lymphoma and colon cancer cell lines. In this study, UCN-01 preferentially enhanced the radiosensitivity of the TP53-disrupted E6 cells compared to the TP53 wild-type cells. This effect was more pronounced in cells synchronized in early G(1) phase, where the E6 cells showed a higher resistance to radiation in the absence of drug. These results indicate that the combination of UCN-01 and radiation can more specifically target resistant TP53 mutated cancer cells and spare TP53 wild-type normal cells.
Xiao
Helen H
HH
Departments of Radiation Oncology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Makeyev
Yan
Y
Butler
James
J
Vikram
Bhadrasain
B
Franklin
William A
WA
D000230:Adenocarcinoma / Q000532:radiotherapy; D000470:Alkaloids / Q000494:pharmacology*; D005434:Flow Cytometry; D016195:G2 Phase; D005720:Gamma Rays; D006801:Humans; D008175:Lung Neoplasms / Q000532:radiotherapy*; D009154:Mutation; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D019311:Staurosporine / Q000031:analogs & derivatives; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D000470:Alkaloids; D011838:Radiation-Sensitizing Agents; D016159:Tumor Suppressor Protein p53; C054852:7-hydroxystaurosporine; D019311:Staurosporine