Similarities and Distinctions in Actions of Surface-Directed and Classic Androgen Receptor Antagonists
Publication Date
September 02, 2015
Journal
PLOS ONE
Authors
Ji Ho Suh, Arundhati Chattopadhyay, Douglas H. Sieglaff, Cheryl Storer Samaniego, et al
Volume
10
Issue
9
Pages
e0137103
DOI
https://dx.plos.org/10.1371/journal.pone.0137103
Publisher URL
http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0137103
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/26332122
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4557941
Europe PMC
http://europepmc.org/abstract/MED/26332122
Web of Science
000360613800097
Scopus
84947811667
Mendeley
http://www.mendeley.com/research/similarities-distinctions-actions-surfacedirected-classic-androgen-receptor-antagonists
Events
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Mendeley | Further Information

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Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/2250781"], "description"=>"<p>Luciferase activity measured in HEK293T cells transfected with Gal4-tk-luc reporter, Gal4-AR LBD or Gal4-GR LBD and treated +/- DHT (1nM) for AR, or +/- Dexamethasone for GR (1nM), and +/- MJC13 (30μM). All data are representative of at least three independent experiments with similar results. All values represent the mean ± SD of duplicate samples. Transfections employed 400ng of Gal4-tk-luc, 200ng of Gal4-AR LBD or 200ng of Gal4-GR LBD and 100ng of β-gal.</p>", "links"=>[], "tags"=>["MJC 13", "generation AR antagonists", "gr", "AR activity", "Classic Androgen Receptor Antagonists", "LNCaP PC cells", "psa", "877A", "mdv", "transfected SRC 2", "22 Rv 1 cells", "Prostate cancer", "crpc", "flutamide withdrawal syndrome", "dht", "ARN"], "article_id"=>1533717, "categories"=>["Biological Sciences"], "users"=>["Ji Ho Suh", "Arundhati Chattopadhyay", "Douglas H. Sieglaff", "Cheryl Storer Samaniego", "Marc B. Cox", "Paul Webb"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0137103.g007", "stats"=>{"downloads"=>0, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_MJC13_does_not_influence_the_GR_LBD_/1533717", "title"=>"MJC13 does not influence the GR LBD.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-09-02 03:16:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/2250780"], "description"=>"<p>(A) Luciferase activity measured in 22RV1 cells transfected with ARE-luc reporter and treated +/- DHT (1nM), +/- Flutamide (1μM), or +/- MJC13 (30μM) overnight, with quantities of plasmids as in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0137103#pone.0137103.g001\" target=\"_blank\">Fig 1A</a>. All data are representative of at least three independent experiments with similar results. All values represent the mean ± SD of duplicate samples. (B-C) qPCR analysis of 22RV1 cells extracts treated +/- DHT (1nM), +/- Flutamide (1μM), or +/- MJC13 (30μM) for 24 hours. The data are representative of at least three independent experiments. All values represent the mean ± SD of triplicate samples. Genes are TMPRSS2 (B) and PSA (C).</p>", "links"=>[], "tags"=>["MJC 13", "generation AR antagonists", "gr", "AR activity", "Classic Androgen Receptor Antagonists", "LNCaP PC cells", "psa", "877A", "mdv", "transfected SRC 2", "22 Rv 1 cells", "Prostate cancer", "crpc", "flutamide withdrawal syndrome", "dht", "ARN"], "article_id"=>1533716, "categories"=>["Biological Sciences"], "users"=>["Ji Ho Suh", "Arundhati Chattopadhyay", "Douglas H. Sieglaff", "Cheryl Storer Samaniego", "Marc B. Cox", "Paul Webb"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0137103.g006", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_AR_antagonists_are_blunted_in_22RV1_cells_/1533716", "title"=>"Effects of AR antagonists are blunted in 22RV1 cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-09-02 03:16:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/2250777"], "description"=>"<p>qPCR analysis of LNCaP cells extracts treated +/- DHT (1nM), +/- Flutamide (1μM), ARN-509, MDV3100 (10μM) or +/- MJC13 (30μM) for 24 hours. The data are representative of at least three independent experiments. All values represent the mean ± SD of triplicate samples. <b>(A)</b> PSA gene. <b>(B)</b> TMPRSS2 gene.</p>", "links"=>[], "tags"=>["MJC 13", "generation AR antagonists", "gr", "AR activity", "Classic Androgen Receptor Antagonists", "LNCaP PC cells", "psa", "877A", "mdv", "transfected SRC 2", "22 Rv 1 cells", "Prostate cancer", "crpc", "flutamide withdrawal syndrome", "dht", "ARN"], "article_id"=>1533713, "categories"=>["Biological Sciences"], "users"=>["Ji Ho Suh", "Arundhati Chattopadhyay", "Douglas H. Sieglaff", "Cheryl Storer Samaniego", "Marc B. Cox", "Paul Webb"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0137103.g003", "stats"=>{"downloads"=>2, "page_views"=>18, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_MJC13_and_Classic_AR_antagonists_display_similar_patterns_of_AR_target_genes_inhibition_/1533713", "title"=>"MJC13 and Classic AR antagonists display similar patterns of AR target genes inhibition.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-09-02 03:16:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/2250776"], "description"=>"<p>Graph representing results of array analysis performed on LNCaP cells treated for 24 hours +/- DHT (1nM), +/- Flutamide (1μM), or +/- MJC13 (30μM) and displaying probe sets in which DHT response is inhibited by MJC13 and Flutamide. The first line (blue) represents DHT responses obtained in the presence of DMSO, second line (orange) represents DHT responses obtained in the presence of Flutamide. The third line (green) represents DHT responses obtained in the presence of MJC13.</p>", "links"=>[], "tags"=>["MJC 13", "generation AR antagonists", "gr", "AR activity", "Classic Androgen Receptor Antagonists", "LNCaP PC cells", "psa", "877A", "mdv", "transfected SRC 2", "22 Rv 1 cells", "Prostate cancer", "crpc", "flutamide withdrawal syndrome", "dht", "ARN"], "article_id"=>1533712, "categories"=>["Biological Sciences"], "users"=>["Ji Ho Suh", "Arundhati Chattopadhyay", "Douglas H. Sieglaff", "Cheryl Storer Samaniego", "Marc B. Cox", "Paul Webb"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0137103.g002", "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_AR_target_genes_are_inhibited_by_MJC13_and_Flutamide_/1533712", "title"=>"AR target genes are inhibited by MJC13 and Flutamide.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-09-02 03:16:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/2250774"], "description"=>"<p>Luciferase activity measured in (A) LNCaP cells transfected with an ARE-luc reporter or (B and C) PC3 and HEK293T cells transfected with an expression vector for AR and the ARE-Luc reporter. Cells were treated with DHT (1nM) +/- increasing doses of Flutamide or MJC13 overnight. Data are representative of at least three independent experiments with similar results. All values represent mean ± SD of duplicate samples. Symbols denoting statistical significance in this figure and ensuing figures are explained in Materials and Methods. The insets show DHT response (black bars) versus vehicle control (arbitrarily set at 1.0; white bars) in each of these experimental conditions. Transfections in Fig 1A employed 200ng of ARE-luc, 100ng of b-gal whereas those in Fig 1B and 1C employed 200ng of ARE-luc, 100ng of AR expression vector and 100ng of β-gal.</p>", "links"=>[], "tags"=>["MJC 13", "generation AR antagonists", "gr", "AR activity", "Classic Androgen Receptor Antagonists", "LNCaP PC cells", "psa", "877A", "mdv", "transfected SRC 2", "22 Rv 1 cells", "Prostate cancer", "crpc", "flutamide withdrawal syndrome", "dht", "ARN"], "article_id"=>1533710, "categories"=>["Biological Sciences"], "users"=>["Ji Ho Suh", "Arundhati Chattopadhyay", "Douglas H. Sieglaff", "Cheryl Storer Samaniego", "Marc B. Cox", "Paul Webb"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0137103.g001", "stats"=>{"downloads"=>1, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_MJC13_inhibits_AR_transactivation_/1533710", "title"=>"MJC13 inhibits AR transactivation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-09-02 03:16:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/2250785", "https://ndownloader.figshare.com/files/2250786", "https://ndownloader.figshare.com/files/2250787", "https://ndownloader.figshare.com/files/2250788"], "description"=>"<div><p>The androgen receptor (AR) surface-directed antagonist MJC13 inhibits AR function and proliferation of prostate cancer (PC) cells. These effects are related to arrest of an AR/chaperone complex in the cytoplasm. Here, we compared MJC13 and classic AR antagonists such as flutamide and bicalutamide. Microarray analysis and confirmatory qRT-PCR reveals that MJC13 and flutamide inhibit dihydrotestosterone (DHT)-dependent genes in LNCaP PC cells. Both compounds are equally effective on a genome wide basis and as effective as second generation AR antagonists (MDV3100, ARN-509) at selected genes. MJC13 inhibits AR binding to the prostate specific antigen (PSA) promoter more strongly than flutamide, consistent with different mechanisms of action. Examination of efficacy of MJC13 in conditions that reflect aspects castrate resistant prostate cancer (CRPC) reveals that it inhibits flutamide activation of an AR mutant (ART877A) that emerges during flutamide withdrawal syndrome, but displays greatly restricted gene-specific activity in 22Rv1 cells that express a constitutively active truncated AR and is inactive against glucocorticoid receptor (GR), which can co-opt androgen-dependent signaling networks in CRPC. Importantly, MJC13 inhibits AR interactions with SRC2 and β-catenin in the nucleus and, unlike flutamide, strongly inhibits amplification of AR activity obtained with transfected SRC2 and β-catenin. MJC13 also inhibits DHT and β-catenin-enhanced cell division in LNCaP cells. Thus, a surface-directed antagonist can block AR activity in some conditions in which a classic antagonist fails and may display utility in particular forms of CRPC.</p></div>", "links"=>[], "tags"=>["MJC 13", "generation AR antagonists", "gr", "AR activity", "Classic Androgen Receptor Antagonists", "LNCaP PC cells", "psa", "877A", "mdv", "transfected SRC 2", "22 Rv 1 cells", "Prostate cancer", "crpc", "flutamide withdrawal syndrome", "dht", "ARN"], "article_id"=>1533721, "categories"=>["Biological Sciences"], "users"=>["Ji Ho Suh", "Arundhati Chattopadhyay", "Douglas H. Sieglaff", "Cheryl Storer Samaniego", "Marc B. Cox", "Paul Webb"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0137103.s001", "https://dx.doi.org/10.1371/journal.pone.0137103.s002", "https://dx.doi.org/10.1371/journal.pone.0137103.s003", "https://dx.doi.org/10.1371/journal.pone.0137103.s004"], "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Similarities_and_Distinctions_in_Actions_of_Surface_Directed_and_Classic_Androgen_Receptor_Antagonists_/1533721", "title"=>"Similarities and Distinctions in Actions of Surface-Directed and Classic Androgen Receptor Antagonists", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2015-09-02 03:16:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/2250783"], "description"=>"<p>Results of luciferase assays performed in HEK293T cells transfected with plasmids of Gal4-AR LBD fusion and SRC-2 (A) or β-catenin (B) and treated +/- DHT (1nM) and +/- Flutamide (1μM) or +/- MJC13 (30μM) overnight. The data are representative of at least three independent experiments. All values represent the mean ± SD of duplicate samples. Transfections employed 100ng of Gal4-tk-luc, 50ng of Gal4-AR LBD, 400ng of SRC-2, 100ng of β-gal in Fig 9A and 100ng of Gal4-tk-luc, 50ng of Gal4-AR LBD, 400ng of b-catenin, 100ng of β-gal in Fig 9B.</p>", "links"=>[], "tags"=>["MJC 13", "generation AR antagonists", "gr", "AR activity", "Classic Androgen Receptor Antagonists", "LNCaP PC cells", "psa", "877A", "mdv", "transfected SRC 2", "22 Rv 1 cells", "Prostate cancer", "crpc", "flutamide withdrawal syndrome", "dht", "ARN"], "article_id"=>1533719, "categories"=>["Biological Sciences"], "users"=>["Ji Ho Suh", "Arundhati Chattopadhyay", "Douglas H. Sieglaff", "Cheryl Storer Samaniego", "Marc B. Cox", "Paul Webb"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0137103.g009", "stats"=>{"downloads"=>0, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_MJC13_inhibits_coactivator_enhanced_AR_activity_/1533719", "title"=>"MJC13 inhibits coactivator-enhanced AR activity.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-09-02 03:16:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/2250784"], "description"=>"<p>LNCaP cells were infected with adenovirus expressing β-catenin (Ad-β-catenin) or null adenovirus (Ad-Null) at multiplicity of infection = 50, and maintained in normal media with steroid depleted serum. Cells were treated +/- DHT (1nM) +/- 1μM Flutamide, Bicalutamide or 30μM MJC13 for 24 h. The absorbance was measured using an ELISA reader at a wavelength of 450 nm. All data are representative of at least three independent experiments with similar results. Values represent the mean ± SD of triplicate samples. *** P < 0.001; ** P < 0.01; * P < 0.05. The shading scheme is as follows: White bars, adenovirus control, squared bars, Ad-β-catenin, black bars, adenovirus control + DHT, striped bars, Ad-β-catenin + DHT.</p>", "links"=>[], "tags"=>["MJC 13", "generation AR antagonists", "gr", "AR activity", "Classic Androgen Receptor Antagonists", "LNCaP PC cells", "psa", "877A", "mdv", "transfected SRC 2", "22 Rv 1 cells", "Prostate cancer", "crpc", "flutamide withdrawal syndrome", "dht", "ARN"], "article_id"=>1533720, "categories"=>["Biological Sciences"], "users"=>["Ji Ho Suh", "Arundhati Chattopadhyay", "Douglas H. Sieglaff", "Cheryl Storer Samaniego", "Marc B. Cox", "Paul Webb"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0137103.g010", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_MJC13_inhibits_946_catenin_induced_LNCaP_cell_proliferation_/1533720", "title"=>"MJC13 inhibits β-catenin-induced LNCaP cell proliferation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-09-02 03:16:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/2250782"], "description"=>"<p>(A) Co-immunoprecipitations from extracts of LNCaP cells treated +/- DHT (1nM), +/- flutamide (1μM), or +/- MJC13 (30μM) for 12 h. AR antibody was used for immunoprecipitation and antibody used for western analysis is indicated at the left hand side. Panels below represent western blots of input proteins or GAPDH loading control. (B) Co-immunoprecipitation assay from extracts of HEK293T cells cotransfected with plasmids of Gal4-AR LBD fusion and SRC-2 or β-catenin. AR LBD was immunoprecipitated with an anti-Gal4 antibody in lysates from cells treated +/- DHT, +/- Flutamide or +/- MJC13 as above. Antibody used for western analysis is indicated at the left hand side. Panels below represent western blots of input proteins or GAPDH loading control.</p>", "links"=>[], "tags"=>["MJC 13", "generation AR antagonists", "gr", "AR activity", "Classic Androgen Receptor Antagonists", "LNCaP PC cells", "psa", "877A", "mdv", "transfected SRC 2", "22 Rv 1 cells", "Prostate cancer", "crpc", "flutamide withdrawal syndrome", "dht", "ARN"], "article_id"=>1533718, "categories"=>["Biological Sciences"], "users"=>["Ji Ho Suh", "Arundhati Chattopadhyay", "Douglas H. Sieglaff", "Cheryl Storer Samaniego", "Marc B. Cox", "Paul Webb"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0137103.g008", "stats"=>{"downloads"=>0, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_MJC13_blocks_AR_interaction_with_coactivators_/1533718", "title"=>"MJC13 blocks AR interaction with coactivators.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-09-02 03:16:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/2250779"], "description"=>"<p>Luciferase activity measured in HEK293T cells transfected with expression vectors for AR WT and AR T877A and an androgen-dependent MMTV-Luc reporter (A) or Gal4-AR LBD and Gal4-AR T877A and a GAL4 responsive reporter gene (B) and treated +/- DHT (1nM), +/- Flutamide (1μM), or +/- MJC13 (30μM) overnight, as in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0137103#pone.0137103.g001\" target=\"_blank\">Fig 1</a>. All data are representative of at least three independent experiments with similar results. All values represent the mean ± SD of duplicate samples. Transfections in Fig 5A employed 200ng of MMTV-luc, 100ng of AR or 100ng of AR T877A expression vectors and 100ng of β-gal whereas those in Fig 5B employed 300ng of Gal4-tk-luc, 200ng of Gal4-AR LBD or 200ng of Gal4-AR LBD T877A and 100ng of β-gal.</p>", "links"=>[], "tags"=>["MJC 13", "generation AR antagonists", "gr", "AR activity", "Classic Androgen Receptor Antagonists", "LNCaP PC cells", "psa", "877A", "mdv", "transfected SRC 2", "22 Rv 1 cells", "Prostate cancer", "crpc", "flutamide withdrawal syndrome", "dht", "ARN"], "article_id"=>1533715, "categories"=>["Biological Sciences"], "users"=>["Ji Ho Suh", "Arundhati Chattopadhyay", "Douglas H. Sieglaff", "Cheryl Storer Samaniego", "Marc B. Cox", "Paul Webb"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0137103.g005", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_MJC13_inhibits_a_flutamide_resistant_AR_mutant_/1533715", "title"=>"MJC13 inhibits a flutamide resistant AR mutant.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-09-02 03:16:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/2250778"], "description"=>"<p>ChIP assays performed in LNCaP cells treated +/- DHT (1nM), +/- Flutamide (1μM), or +/- MJC13 (30μM) for 16 hours. Antibodies used for immunoprecipitation were AR or IgG control. 10% (v/v) of the supernatant was represented as ‘input’ chromatin prior to immunoprecipitation by antibodies.</p>", "links"=>[], "tags"=>["MJC 13", "generation AR antagonists", "gr", "AR activity", "Classic Androgen Receptor Antagonists", "LNCaP PC cells", "psa", "877A", "mdv", "transfected SRC 2", "22 Rv 1 cells", "Prostate cancer", "crpc", "flutamide withdrawal syndrome", "dht", "ARN"], "article_id"=>1533714, "categories"=>["Biological Sciences"], "users"=>["Ji Ho Suh", "Arundhati Chattopadhyay", "Douglas H. Sieglaff", "Cheryl Storer Samaniego", "Marc B. Cox", "Paul Webb"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0137103.g004", "stats"=>{"downloads"=>0, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_MJC13_suppresses_AR_recruitment_to_an_ARE_/1533714", "title"=>"MJC13 suppresses AR recruitment to an ARE.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-09-02 03:16:03"}

PMC Usage Stats | Further Information

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Relative Metric

{"start_date"=>"2015-01-01T00:00:00Z", "end_date"=>"2015-12-31T00:00:00Z", "subject_areas"=>[]}
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