期刊
NUCLEIC ACIDS RESEARCH
卷 42, 期 9, 页码 5689-5701出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gku217
关键词
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资金
- EMBO short-term fellowship
- ARC foundation
- Israel Science Foundation (ISF) [684/13]
- AFHU
- Agence nationale de la recherche (program Blanc, Chromarep)
- Centre National de la Recherche Scientifique (CNRS, ATIP)
- Institut national du cancer (INCA libre) [2009-195]
- European FP7 framework (Marie Curie Reintegration grant)
- Fondation Schlumberger (FSER)
- National Institutes of Health (NIH) [CA100839, DA033981, MH097512]
- US-Israel bi-national fund (BSF) [2011262]
- Division Of Physics
- Direct For Mathematical & Physical Scien [2011262] Funding Source: National Science Foundation
DNA double-strand breaks (DSBs) are the most severe type of DNA damage. DSBs are repaired by non-homologous end-joining or homology directed repair (HDR). Identifying novel small molecules that affect HDR is of great importance both for research use and therapy. Molecules that elevate HDR may improve gene targeting whereas inhibiting molecules can be used for chemotherapy, since some of the cancers are more sensitive to repair impairment. Here, we performed a high-throughput chemical screen for FDA approved drugs, which affect HDR in cancer cells. We found that HDR frequencies are increased by retinoic acid and Idoxuridine and reduced by the antihypertensive drug Spironolactone. We further revealed that Spironolactone impairs Rad51 foci formation, sensitizes cancer cells to DNA damaging agents, to Poly (ADP-ribose) polymerase (PARP) inhibitors and cross-linking agents and inhibits tumor growth in xenografts, in mice. This study suggests Spironolactone as a new candidate for chemotherapy.
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