DNA-PK inhibitor wortmannin enhances DNA damage induced by bleomycin in V79 Chinese hamster cells

• Published in: Teratogenesis, carcinogenesis, and mutagenesis carcinogenesis, and mutagenesis, 2002, Vol.22 (5), p.343-351
• Main Authors: Oliveira, Nuno G., Castro, Matilde, Rodrigues, António S., Gil, Octávia M., Toscano-Rico, José M., Rueff, José
• Format: Article
• Language: English
• Subjects: Androstadienes - pharmacology; Animals; Antibiotics, Antineoplastic - pharmacology; Antineoplastic agents; Biological and medical sciences; bleomycin; Bleomycin - pharmacology; Cell Division; Cell Line; Chemotherapy; Cricetinae; cytokinesis-block micronucleus assay; DNA Damage; DNA-dependent protein kinase (DNA-PK); Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; Medical sciences; Micronuclei, Chromosome-Defective - metabolism; non-homologous end-joining (NHEJ); Pharmacology. Drug treatments; V79 Chinese hamster cells; wortmannin
• ISSN: 0270-3211; 1520-6866
• DOI: 10.1002/tcm.10029

The fungal metabolite wortmannin (WM) is a potent and irreversible inhibitor of the enzyme DNA‐dependent protein kinase (DNA‐PK), a nuclear serine‐threonine kinase, member of the phosphaditylinositol‐3 kinase related kinase family. WM has been used in the last few years as a promising radiosensitizer mainly throughout cell survival experiments. However, few studies have addressed the role of DNA‐PK inhibition in the repair of DNA lesions generated by antitumor agents. Bleomycin (BLM) is an antitumor agent used in the treatment of various neoplasia with a unique genotoxicity profile that mimics the ionizing radiation effects. In this study, we evaluated the effect of different concentrations of WM on the DNA damage induced by BLM. The cytokinesis‐block micronucleus assay (CBMN) in V79 Chinese hamster cells was used as the end‐point. WM significantly increased the frequency of micronucleated cells (%MNBN) by about 2.2‐fold, the number of micronuclei per binucleated cell (MN/BN) by about 2.4‐fold, and also changed the pattern of the distribution of micronuclei induced by BLM. The frequency of micronucleated cells with 2 MN per cell and with ≥3 MN per cell increased, whereas the frequency of micronucleated cells with 1 MN per cell decreased. WM was not genotoxic but decreased cell proliferation as assessed by the frequency of binucleated cells. Our results show that WM clearly enhances the efficacy of BLM in terms of DNA damage inflicted and therefore reinforces its use as a chemosensitizer. Teratogenesis Carcinog. Mutagen. 22:343–351, 2002. © 2002 Wiley‐Liss, Inc.