A high-throughput chemical screen with FDA approved drugs reveals that the antihypertensive drug Spironolactone impairs cancer cell survival by inhibiting homology directed repair

Or David Shahar; Alkmini Kalousi; Lital Eini; Benoit Fisher; Amelie Weiss; Jonatan Darr; Olga Mazina; Shay Bramson; Martin Kupiec; Amir Eden; Eran Meshorer; Alexander V. Mazin; Laurent Brino; Michal Goldberg; Evi Soutoglou

doi:10.1093/nar/gku217

A high-throughput chemical screen with FDA approved drugs reveals that the antihypertensive drug Spironolactone impairs cancer cell survival by inhibiting homology directed repair

Or David Shahar, Alkmini Kalousi, Lital Eini, Benoit Fisher, Amelie Weiss, Jonatan Darr, Olga Mazina, Shay Bramson, Martin Kupiec, Amir Eden, Eran Meshorer, Alexander V. Mazin, Laurent Brino, Michal Goldberg^*, Evi Soutoglou

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

37 Scopus citations

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.

Original language	English
Pages (from-to)	5689-5701
Number of pages	13
Journal	Nucleic Acids Research
Volume	42
Issue number	9
DOIs	https://doi.org/10.1093/nar/gku217
State	Published - May 2014

Bibliographical note

Funding Information:
EMBO short-term fellowship (to O.D.S). ARC foundation (to A.K.). Israel Science Foundation (ISF) [684/13]; AFHU (to M.G). Agence nationale de la recherché (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) (to E.S.). National Institutes of Health (NIH) [CA100839, DA033981, MH097512] (to A.V.M.]); US-Israel bi-national fund (BSF) [2011262] (to M.K.). Conflict of interest statement. None declared.

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10.1093/nar/gku217

Cite this

Shahar, O. D., Kalousi, A., Eini, L., Fisher, B., Weiss, A., Darr, J., Mazina, O., Bramson, S., Kupiec, M., Eden, A., Meshorer, E., Mazin, A. V., Brino, L., Goldberg, M., & Soutoglou, E. (2014). 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, 42(9), 5689-5701. https://doi.org/10.1093/nar/gku217

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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",

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.",

author = "Shahar, {Or David} and Alkmini Kalousi and Lital Eini and Benoit Fisher and Amelie Weiss and Jonatan Darr and Olga Mazina and Shay Bramson and Martin Kupiec and Amir Eden and Eran Meshorer and Mazin, {Alexander V.} and Laurent Brino and Michal Goldberg and Evi Soutoglou",

note = "Funding Information: EMBO short-term fellowship (to O.D.S). ARC foundation (to A.K.). Israel Science Foundation (ISF) [684/13]; AFHU (to M.G). Agence nationale de la recherch{\'e} (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) (to E.S.). National Institutes of Health (NIH) [CA100839, DA033981, MH097512] (to A.V.M.]); US-Israel bi-national fund (BSF) [2011262] (to M.K.). Conflict of interest statement. None declared.",

year = "2014",

month = may,

doi = "10.1093/nar/gku217",

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Shahar, OD, Kalousi, A, Eini, L, Fisher, B, Weiss, A, Darr, J, Mazina, O, Bramson, S, Kupiec, M, Eden, A , Meshorer, E, Mazin, AV, Brino, L, Goldberg, M & Soutoglou, E 2014, '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, vol. 42, no. 9, pp. 5689-5701. https://doi.org/10.1093/nar/gku217

A high-throughput chemical screen with FDA approved drugs reveals that the antihypertensive drug Spironolactone impairs cancer cell survival by inhibiting homology directed repair. / Shahar, Or David; Kalousi, Alkmini; Eini, Lital et al.
In: Nucleic Acids Research, Vol. 42, No. 9, 05.2014, p. 5689-5701.

Research output: Contribution to journal › Article › peer-review

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T1 - A high-throughput chemical screen with FDA approved drugs reveals that the antihypertensive drug Spironolactone impairs cancer cell survival by inhibiting homology directed repair

AU - Shahar, Or David

AU - Kalousi, Alkmini

AU - Eini, Lital

AU - Fisher, Benoit

AU - Weiss, Amelie

AU - Darr, Jonatan

AU - Mazina, Olga

AU - Bramson, Shay

AU - Kupiec, Martin

AU - Eden, Amir

AU - Meshorer, Eran

AU - Mazin, Alexander V.

AU - Brino, Laurent

AU - Goldberg, Michal

AU - Soutoglou, Evi

N1 - Funding Information: EMBO short-term fellowship (to O.D.S). ARC foundation (to A.K.). Israel Science Foundation (ISF) [684/13]; AFHU (to M.G). Agence nationale de la recherché (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) (to E.S.). National Institutes of Health (NIH) [CA100839, DA033981, MH097512] (to A.V.M.]); US-Israel bi-national fund (BSF) [2011262] (to M.K.). Conflict of interest statement. None declared.

PY - 2014/5

Y1 - 2014/5

N2 - 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.

AB - 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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A high-throughput chemical screen with FDA approved drugs reveals that the antihypertensive drug Spironolactone impairs cancer cell survival by inhibiting homology directed repair

Abstract

Bibliographical note

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