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Journal article
A high-throughput chemical screen with FDA approved drugs reveals that the antihypertensive drug Spironolactone impairs cancer cell survival by inhibiting homology directed repair
Nucleic acids research, v 42(9), pp 5689-5701
01 Jan 2014
PMID: 24682826
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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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- Title
- A high-throughput chemical screen with FDA approved drugs reveals that the antihypertensive drug Spironolactone impairs cancer cell survival by inhibiting homology directed repair
- Creators
- Or David Shahar - Hebrew University of JerusalemAlkmini Kalousi - Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), UMR 7104 CNRS, UdS, INSERM U964, BP 10142, F-67404 Illkirch Cedex, CU de Strasbourg, FranceLital Eini - Hebrew University of JerusalemBenoit Fisher - Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), UMR 7104 CNRS, UdS, INSERM U964, BP 10142, F-67404 Illkirch Cedex, CU de Strasbourg, FranceAmelie Weiss - Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), UMR 7104 CNRS, UdS, INSERM U964, BP 10142, F-67404 Illkirch Cedex, CU de Strasbourg, FranceJonatan Darr - Hebrew University of JerusalemOlga Mazina - Drexel UniversityShay Bramson - Tel Aviv UniversityMartin Kupiec - Tel Aviv UniversityAmir Eden - Hebrew University of JerusalemEran Meshorer - Hebrew University of JerusalemAlexander V. Mazin - Drexel UniversityLaurent Brino - Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), UMR 7104 CNRS, UdS, INSERM U964, BP 10142, F-67404 Illkirch Cedex, CU de Strasbourg, FranceMichal Goldberg - Hebrew University of JerusalemEvi Soutoglou - Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), UMR 7104 CNRS, UdS, INSERM U964, BP 10142, F-67404 Illkirch Cedex, CU de Strasbourg, France
- Publication Details
- Nucleic acids research, v 42(9), pp 5689-5701
- Publisher
- Oxford Univ Press
- Number of pages
- 13
- Grant note
- Agence nationale de la recherche (program Blanc, Chromarep); French National Research Agency (ANR) ARC foundation; Australian Research Council Centre National de la Recherche Scientifique (CNRS, ATIP); Centre National de la Recherche Scientifique (CNRS) Fondation Schlumberger (FSER) 2011262 / US-Israel bi-national fund (BSF); US-Israel Binational Science Foundation 684/13 / Israel Science Foundation (ISF); Israel Science Foundation EMBO short-term fellowship; European Molecular Biology Organization (EMBO) AFHU R03MH097512 / NATIONAL INSTITUTE OF MENTAL HEALTH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Mental Health (NIMH) European FP7 framework (Marie Curie Reintegration grant) P30CA056036 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) 2009-195 / Institut national du cancer (INCA libre) CA100839; DA033981; MH097512 / National Institutes of Health (NIH); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R03DA033981 / NATIONAL INSTITUTE ON DRUG ABUSE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Drug Abuse (NIDA); European Commission
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000336495400032
- Scopus ID
- 2-s2.0-84901336187
- Other Identifier
- 991019168651804721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology