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.
authors.affiliation: Department of Genetics, Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem 91904, Israel.
authors.forename: Or David
authors.initials: OD
authors.lastname: Shahar
authors.affiliation: 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.
authors.forename: Alkmini
authors.initials: A
authors.lastname: Kalousi
authors.affiliation: Department of Genetics, Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem 91904, Israel.
authors.forename: Lital
authors.initials: L
authors.lastname: Eini
authors.affiliation: 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.
authors.forename: Benoit
authors.initials: B
authors.lastname: Fisher
authors.affiliation: 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.
authors.forename: Amelie
authors.initials: A
authors.lastname: Weiss
authors.affiliation: Department of Genetics, Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem 91904, Israel.
authors.forename: Jonatan
authors.initials: J
authors.lastname: Darr
authors.affiliation: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Mazina
authors.affiliation: Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Ramat Aviv 69978, Israel.
authors.forename: Shay
authors.initials: S
authors.lastname: Bramson
authors.affiliation: Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Ramat Aviv 69978, Israel.
authors.forename: Martin
authors.initials: M
authors.lastname: Kupiec
authors.affiliation: Department of Genetics, Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem 91904, Israel.
authors.forename: Amir
authors.initials: A
authors.lastname: Eden
authors.affiliation: Department of Genetics, Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem 91904, Israel.
authors.forename: Eran
authors.initials: E
authors.lastname: Meshorer
authors.affiliation: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Mazin
authors.affiliation: 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.
authors.forename: Laurent
authors.initials: L
authors.lastname: Brino
authors.affiliation: Department of Genetics, Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem 91904, Israel evisou@igbmc.fr.
authors.forename: Michal
authors.initials: M
authors.lastname: Goldberg
authors.affiliation: 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 evisou@igbmc.fr.
authors.forename: Evi
authors.initials: E
authors.lastname: Soutoglou
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D053903:DNA Breaks, Double-Stranded; D004311:Double-Blind Method; D017277:Drug Approval; D057166:High-Throughput Screening Assays; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D051135:Rad51 Recombinase / Q000378:metabolism; D059767:Recombinational DNA Repair / Q000187:drug effects*; D013148:Spironolactone / Q000494:pharmacology*; D014481:United States; D014486:United States Food and Drug Administration; D023041:Xenograft Model Antitumor Assays
chemical_list: D000959:Antihypertensive Agents; D000970:Antineoplastic Agents; D013148:Spironolactone; C495153:RAD51 protein, human; D051135:Rad51 Recombinase