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PARP inhibition potentiates the cytotoxic activity of C-1305, a selective inhibitor of topoisomerase II, in human BRCA1-positive breast cancer cells
Abstract
Two cellular proteins encoded by the breast and ovarian cancer type 1 susceptibility (BRCA1 and BRCA2) tumor suppressor genes are essential for DNA integrity and the maintenance of genomic stability.Approximately 5-10% of breast and ovarian cancers result from inherited alterations or mutations in these genes.Remarkably, BRCA1/BRCA2-deficient cells are hypersensitive to selective inhibition of poly(ADPribose) polymerase 1 (PARP-1), whose primary functions are related to DNA base excision repair; PARP-1inhibition significantly potentiates the cytotoxicity of various anti-cancer drugs, including inhibitors of topoisomerase I and II. In the present study, we examined the anti-proliferative and pro-apoptotic effects of C-1305, a selective inhibitor of topoisomerase II, on human breast cancer cell lines with different BRCA1 and p53 statuses. BRCA1-competent breast cancer cell lines exhibited different responses to topoisomerase II inhibition. BT-20 cells that express high levels of BRCA1 levels were most resistant to C-1305 than other tested cells. Surprisingly, pharmacological interference with PARP-1 activity strongly inhibited their proliferation and potentiated the efficacy of C-1305 treatment. In contrast, PARP-1 inhibition only weakly affected the proliferation of BRCA1-deficient SKBr-3 cells and was not synergistic with the effects of C-1305. Further experiments revealed that the inhibition of PARP-1 in BT-20 cells caused the accumulation of DNA strand breaks and induced caspase-3 dependent apoptosis. These results seem to indicate that PARP-1 inhibition can potentiate the cytotoxicity of anti-cancer drugs in cancer cells with functional BRCA1 and suggest that mutations in other DNA repair proteins may render cancer cells more sensitive to interference with PARP-1 activity.
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- Category:
- Articles
- Type:
- artykuł w czasopiśmie wyróżnionym w JCR
- Published in:
-
BIOCHEMICAL PHARMACOLOGY
no. 84,
pages 1318 - 1331,
ISSN: 0006-2952 - Language:
- English
- Publication year:
- 2012
- Bibliographic description:
- Węsierska-Gądek J., Zulehner N., Ferk F., Składanowski A., Komina O., Maurer M.: PARP inhibition potentiates the cytotoxic activity of C-1305, a selective inhibitor of topoisomerase II, in human BRCA1-positive breast cancer cells// BIOCHEMICAL PHARMACOLOGY. -Vol. 84, nr. iss. 10 (2012), s.1318-1331
- DOI:
- Digital Object Identifier (open in new tab) 10.1016/j.bcp.2012.07.024
- Verified by:
- Gdańsk University of Technology
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