Radiosensitization and inhibition of deoxyribonucleic acid repair in rat glioma cells by long-term treatment with 12-O-tetradecanoylphorbol 13-acetate.
Patients with brain tumors often undergo radiotherapy, and the cellular resistance is a major obstacle. It has been suggested that protein kinase C (PKC) may be one of a number of important regulatory enzymes in cell response to ionizing radiation. We therefore investigated the effect of PKC depletion on deoxyribonucleic acid (DNA) damage and repair after radiation in C6 cells using a microgel electrophoresis method to explore the role of PKC in glioma radioresistance. When cells are embedded in agarose on slides, lysed, and subjected to an electric field, broken DNA is able to migrate toward the anode. A significant increase in the length of DNA migration was observed in the cells exposed to irradiation. Inhibition of PKC activity by prolonged treatment with 12-O-tetradecanoylphorbol 13-acetate (TPA) or staurosporine, a potent PKC inhibitor, before irradiation enhanced radiation-induced DNA damage and attenuated the repair of damaged DNA. The half-times of DNA repair in parent C6 cells and PKC-depleted C6 cells were about 30 and 60 min, respectively, and the extent of DNA migration was still seen in the PKC-depleted cells even at 120 min after irradiation. In addition, the C6 cell clonogenicity after irradiation was also attenuated by long-term exposure of the cells to 12-O-tetradecanoylphorbol 13-acetate. These data suggest that PKC may play an important role in regulating the cell response to irradiation. The inhibitors of PKC might represent a new class of pharmacological agents to manipulate the radiosensitivity of gliomas.
Zhang
W
W
Department of Neurosurgery, Gifu University School of Medicine, Japan.
Hara
A
A
Sakai
N
N
Andoh
T
T
Yamada
H
H
Nozawa
Y
Y
D000818:Animals; D001932:Brain Neoplasms / Q000473:pathology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology; D004260:DNA Repair / Q000187:drug effects / Q000502:physiology; D004273:DNA, Neoplasm / Q000528:radiation effects*; D005910:Glioma / Q000473:pathology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D051381:Rats; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects*; D014410:Tumor Stem Cell Assay
D004273:DNA, Neoplasm; D011838:Radiation-Sensitizing Agents; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate