title: Bufalin is a potent small-molecule inhibitor of the steroid receptor coactivators SRC-3 and SRC-1.
abstract: Virtually all transcription factors partner with coactivators that recruit chromatin remodeling factors and interact with the basal transcription machinery. Coactivators have been implicated in cancer cell proliferation, invasion, and metastasis, including the p160 steroid receptor coactivator (SRC) family composed of SRC-1 (NCOA1), SRC-2 (TIF2/GRIP1/NCOA2), and SRC-3 (AIB1/ACTR/NCOA3). Given their broad involvement in many cancers, they represent candidate molecular targets for new chemotherapeutics. Here, we report on the results of a high-throughput screening effort that identified the cardiac glycoside bufalin as a potent small-molecule inhibitor for SRC-3 and SRC-1. Bufalin strongly promoted SRC-3 protein degradation and was able to block cancer cell growth at nanomolar concentrations. When incorporated into a nanoparticle delivery system, bufalin was able to reduce tumor growth in a mouse xenograft model of breast cancer. Our work identifies bufalin as a potentially broad-spectrum small-molecule inhibitor for cancer.
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Lonard
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Dar-Chone
authors.initials: DC
authors.lastname: Chow
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Palzkill
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Ruogu
authors.initials: R
authors.lastname: Qi
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Matzuk
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Xianzhou
authors.initials: X
authors.lastname: Song
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA.
authors.forename: Franck
authors.initials: F
authors.lastname: Madoux
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Hodder
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Chase
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Griffin
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Suoling
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Liao
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Jianming
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Bert W
authors.initials: BW
authors.lastname: O'Malley
mesh_terms: D000818:Animals; D002018:Bufanolides / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004077:Digoxin / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D016513:Mice, SCID; D056920:Nuclear Receptor Coactivator 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D056921:Nuclear Receptor Coactivator 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D002018:Bufanolides; D014157:Transcription Factors; D004077:Digoxin; C538866:NCOA3 protein, human; D056920:Nuclear Receptor Coactivator 1; D056921:Nuclear Receptor Coactivator 3; C022777:bufalin