A phosphatidylinositol 3‐kinase inhibitor wortmannin induces radioresistant DNA synthesis and sensitizes cells to bleomycin and ionizing radiation

• Published in: International journal of cancer 1998-11, Vol.78 (5), p.642-647
• Main Authors: Hosoi, Yoshio, Miyachi, Hideo, Matsumoto, Yoshihisa, Ikehata, Hironobu, Komura, Jun‐ichiro, Ishii, Keiichiro, Zhao, Heng‐Jiang, Yoshida, Masayuki, Takai, Yoshihiro, Yamada, Shougo, Suzuki, Norio, Ono, Tetsuya
• Format: Article
• Language: English
• Subjects: Androstadienes - pharmacology; Animals; Antibiotics, Antineoplastic - pharmacology; Antineoplastic agents; Ataxia Telangiectasia Mutated Proteins; Biological and medical sciences; Bleomycin - pharmacology; Cell Cycle Proteins; Chemotherapy; DNA - biosynthesis; DNA-Activated Protein Kinase; DNA-Binding Proteins; Enzyme Inhibitors - pharmacology; Humans; Medical sciences; Mice; Mice, SCID; Nuclear Proteins; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Proteins - analysis; Radiation therapy and radiosensitizing agent; Radiation-Sensitizing Agents - pharmacology; Treatment with physical agents; Treatment. General aspects; Tumor Cells, Cultured; Tumor Suppressor Proteins; Tumors; Wortmannin
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/(SICI)1097-0215(19981123)78:5<642::AID-IJC19>3.0.CO;2-3

ATM and DNA‐dependent protein kinase catalytic subunit (DNA‐PKcs) have been shown to have sequences homologous to the catalytic domains of mammalian phosphatidylinositol 3‐kinase (PI3‐kinase). In order to determine the contribution of ATM and DNA‐PKcs to the increased sensitivity of cells to DNA‐damaging agents observed in the presence of PI3‐kinase inhibitors, we examined the effects of a PI3‐kinase inhibitor, wortmannin, on cellular sensitivity to bleomycin (BLM), mitomycin C (MMC), X‐irradiation and ultraviolet (UV)‐irradiation using 2 human tumor cell lines (T98G and A172), a human fibroblast cell line (LM217), an ataxia telangiectasia (AT) cell line (AT3BISV), a scid murine cell line (SCF) and a control murine cell line (CBF). Wortmannin sensitized all of the cells, including AT3BISV and SCF, to BLM and X‐irradiation, but not to MMC or UV‐irradiation. Hypersensitivity to BLM and X‐irradiation and normal sensitivity to MMC and UV‐irradiation are characteristic phenotypes of both AT and scid mice. DNA‐dependent protein kinase (DNA‐PK) activity was suppressed by wortmannin to 45–65% of the control values in all of the cells except SCF, in which DNA‐PK activity was not detected. Wortmannin also induced radioresistant DNA synthesis, which is a cellular phenotype of AT, in T98G and SCF cells, but did not change the DNA synthesis rates after X‐irradiation in AT3BISV. Our data suggest that wortmannin decreases the activities of both the ATM protein and DNA‐PK, indicating that it might be of use as a sensitizing agent for radiotherapy and chemotherapy. Int. J. Cancer 78:642–647, 1998. © 1998 Wiley‐Liss, Inc.