Effectiveness of the Histone Deacetylase Inhibitor (S)-2 against LNCaP and PC3 Human Prostate Cancer Cells
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{"title"=>"Design, synthesis and preliminary evaluation of a series of histone deacetylase inhibitors carrying a benzodiazepine ring", "type"=>"journal", "authors"=>[{"first_name"=>"L.", "last_name"=>"Guandalini", "scopus_author_id"=>"6602704310"}, {"first_name"=>"M.", "last_name"=>"Balliu", "scopus_author_id"=>"33567548500"}, {"first_name"=>"C.", "last_name"=>"Cellai", "scopus_author_id"=>"6603319328"}, {"first_name"=>"M. V.", "last_name"=>"Martino", "scopus_author_id"=>"56566165900"}, {"first_name"=>"A.", "last_name"=>"Nebbioso", "scopus_author_id"=>"8905019900"}, {"first_name"=>"C.", "last_name"=>"Mercurio", "scopus_author_id"=>"6602705336"}, {"first_name"=>"V.", "last_name"=>"Carafa", "scopus_author_id"=>"23388367600"}, {"first_name"=>"G.", "last_name"=>"Bartolucci", "scopus_author_id"=>"35876383700"}, {"first_name"=>"S.", "last_name"=>"Dei", "scopus_author_id"=>"6603690779"}, {"first_name"=>"D.", "last_name"=>"Manetti", "scopus_author_id"=>"6602098836"}, {"first_name"=>"E.", "last_name"=>"Teodori", "scopus_author_id"=>"7003421381"}, {"first_name"=>"S.", "last_name"=>"Scapecchi", "scopus_author_id"=>"7004453434"}, {"first_name"=>"L.", "last_name"=>"Altucci", "scopus_author_id"=>"6701785805"}, {"first_name"=>"F.", "last_name"=>"Paoletti", "scopus_author_id"=>"7007075757"}, {"first_name"=>"M. N.", "last_name"=>"Romanelli", "scopus_author_id"=>"7006303489"}], "year"=>2013, "source"=>"European Journal of Medicinal Chemistry", "identifiers"=>{"scopus"=>"2-s2.0-84925234100", "sgr"=>"84925234100", "issn"=>"17683254", "doi"=>"10.1371/journal.pone.0058267", "pii"=>"S0223523413003176", "pmid"=>"23792316", "pui"=>"603099324"}, "keywords"=>["1,4-Benzodiazepine", "Antiproliferative activity", "Apoptosis", "Enantioselectivity", "HDAC inhibitors"], "id"=>"081a05ee-a513-3270-9c19-3a97f9e558e9", "abstract"=>"A series of new histone deacetylase inhibitors were designed and synthesized based on hybridization between SAHA or oxamflatin and 5-phenyl-1,4-benzodiazepines. The compounds were tested for their enzyme inhibitory activity on HeLa nuclear extracts, and on human recombinant HDAC1 and HDAC6. Antiproliferative activity was tested on different cancer cells types, while proapoptotic activity was primarily tested on NB4 cells. The compounds showed IC50 values similar to those of SAHA. Compound (S)-8 displayed interesting activity against hematological and solid malignancies.", "link"=>"http://www.mendeley.com/research/design-synthesis-preliminary-evaluation-series-histone-deacetylase-inhibitors-carrying-benzodiazepin-1", "reader_count"=>12, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>1, "Librarian"=>1, "Researcher"=>2, "Student > Ph. D. Student"=>3, "Student > Postgraduate"=>1, "Student > Bachelor"=>4}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>1, "Librarian"=>1, "Researcher"=>2, "Student > Ph. D. Student"=>3, "Student > Postgraduate"=>1, "Student > Bachelor"=>4}, "reader_count_by_subject_area"=>{"Agricultural and Biological Sciences"=>1, "Medicine and Dentistry"=>3, "Pharmacology, Toxicology and Pharmaceutical Science"=>2, "Chemistry"=>6}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>3}, "Chemistry"=>{"Chemistry"=>6}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>1}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>2}}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/976997"], "description"=>"<p>(<b>A</b>) <b>–</b> Cells (10<sup>5</sup>) were seeded in 6-well plates and allowed to attach overnight. The day after (S)-2 was added at the indicated concentrations and cell number was determined along the next three days. (<b>B</b>) – Cells were incubated for 24 h with 2.5 µM (S)-2 to determine the % of PI-stained cells in different phases of the cell cycle as determined by flow cytometry. Pictures of either untreated and treated cultures were taken with the aid of a phase-contrast microscopy. (<b>C</b>) <b>–</b> p21 mRNA levels in PC3 cells from cultures treated without/with (S)-2 were measured by quantitative real-time PCR. (<b>D</b>) <b>–</b> Comparative Western blot analysis of acetyl-H3 levels in cell extracts from PC3 treated with either (S)-2 or SAHA; α-tubulin was used as loading control.</p>", "links"=>[], "tags"=>["cells"], "article_id"=>644328, "categories"=>["Chemistry", "Cancer", "Cell Biology"], "users"=>["Anna Laurenzana", "Manjola Balliu", "Cristina Cellai", "Maria Novella Romanelli", "Francesco Paoletti"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0058267.g004", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_PC3_cells_undergo_growth_arrest_upon_treatment_with_S_2_/644328", "title"=>"PC3 cells undergo growth arrest upon treatment with (S)-2.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-03-05 10:37:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/976988"], "description"=>"<p>(<b>A</b>) – LNCAP and PNT1A cells were incubated for 24 h with increasing amounts of either (S)-2 and SAHA. Cell extracts were subjected to Western immunoblotting to detect phospho-H2AX, PARP and its cleaved fragment and acetyl-H3; α-tubulin was used as loading control. (<b>B</b>) <b>–</b> p21 mRNA levels from LNCAP and PNT1A cells incubated without/with (S)-2 or SAHA for 24 h were measured by quantitative real-time PCR. Normal PNT1A cells were apparently less sensitive to (S)-2 as compared to SAHA. Columns, average of three independent samples: bars ± SD; significant difference (<i>P</i>≤0.05). (<b>C</b>) <b>–</b> PARP cleavage and γ-H2AX levels induced in LNCaP and PNT1A cells by a 24 h-treatment without/with (S)-2 were compared on the same blot.</p>", "links"=>[], "tags"=>["saha", "lncap", "pnt1a"], "article_id"=>644323, "categories"=>["Chemistry", "Cancer", "Cell Biology"], "users"=>["Anna Laurenzana", "Manjola Balliu", "Cristina Cellai", "Maria Novella Romanelli", "Francesco Paoletti"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0058267.g003", "stats"=>{"downloads"=>0, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_S_2_and_SAHA_towards_LNCAP_and_PNT1A_cells_/644323", "title"=>"Effects of (S)-2 and SAHA towards LNCAP and PNT1A cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-03-05 10:35:58"}
  • {"files"=>["https://ndownloader.figshare.com/files/976987"], "description"=>"<p>(<b>A</b>) <b>–</b> Cells were incubated with the drug (2.5, 5 µM) for the indicated time points. Whole-cell extracts were analysed by Western immunoblot to detect: phospho-H2AX, that it is triggered following DNA damage; PARP and its cleaved fragment to denote apoptotic activaction; and acetyl-H4 due to the inhibition of HDAC activity. GAPDH and α-tubulin were used as loading controls. (<b>B</b>) <b>–</b> Untreated or drug-treated cells (2.5 µM for 48 h) were incubated during the the last 60 min with FAM-DEVD-FMK carboxyfluoresceine, then rinsed twice with PBS and their green fluorescence was measured by flow cytometry. The frequency histogram of the number of events (Y axis) <i>versus</i> fluorescein intensity (X axis) showed two peaks: caspase-negative cells (unlabeled cells) were on the left of the P2 region; while caspase-positive cells which were labeled with Flica occurred within the P2 region. (<b>C</b>) – Treatment with (S)-2 led to a dose-dependent mitochondrial transmembrane potential (ΔΨ) dissipation. This effect was assessed with the aid of JC-1 dye, which aggregates in normal mitochondria and emits red fluorescence but it can not accumulate in mitochondria which have lost their transmembrane potential, and, therefore emits a diffuse cytoplasmatic green signal in dead cells. Mitochondrial depolarization is indicated by a decrease in the red/green (R/G) fluorescence intensity ratio <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058267#pone.0058267-Salvioli1\" target=\"_blank\">[32]</a>. Values have been normalized by using the control signal (only the vehicle) as an arbitrary value of 100%. Each bar is the mean of two independent experiments performed in triplicate. (<b>D</b>) <b>–</b> LNCAP cells were treated with (S)-2 (2.5–5 µM) or with (S)-2 (5 µM) plus 15 mM N-Acetyl Cysteine (NAC) applied 2 h before drug addition. Activation of apoptosis was revealed by the cleavage of PARP and phosphorylation of H2AX and these events as well as the drug-mediated α-tubulin acetylation were not contrasted by NAC. GAPDH was used as the reference protein. (<b>E</b>) – Z-VAD-fmk prevented the drug-induced cleavage of PARP and the phosphorylation of H2AX. LNCAP cells were treated as above but, instead of NAC, cultures were preincubated with 30 µM Z-VAD-fmk for 2 h prior to be treated for 24 h with the drug. Cell lysates were analyzed for the cleavage of PARP, the activation of caspase 3 and 9, H2AX phosphorylation as well as acetylation of H4 and α-tubulin; α-tubulin was used as loading control.</p>", "links"=>[], "tags"=>["induced", "apoptosis", "lncap"], "article_id"=>644322, "categories"=>["Chemistry", "Cancer", "Cell Biology"], "users"=>["Anna Laurenzana", "Manjola Balliu", "Cristina Cellai", "Maria Novella Romanelli", "Francesco Paoletti"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0058267.g002", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_S_2_induced_apoptosis_in_LNCaP_cells_/644322", "title"=>"(S)-2 induced apoptosis in LNCaP cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-03-05 10:35:26"}
  • {"files"=>["https://ndownloader.figshare.com/files/977004"], "description"=>"<p>(<b>A</b>) <b>–</b> Aliquots of conditioned media from PC3 cultures incubated without/with (S)-2 in the absence of FCS were submitted to gelatin zymography and densitometric analysis of MMP-9 activity (percentage of control). (<b>B</b>) <b>–</b> MMP-9 and TIMP-1 mRNA levels from PC3 cells treated without/with (S)-2 for 24 h were determined by quantitative real-time PCR. (<b>C</b>) <b>–</b> (S)-2 inhibited PC3 cell motility <i>in vitro</i>. Confluent cultures were “wounded” with the aid of a sterile plastic tip and maintained without/with increasing amounts of drug for 24 h. A phase-contrast microscopy was used to take pictures of the monolayers. (<b>D</b>) – (S)-2 decreased invasiveness of PC3. Cultures were pre-treated with/without (S)-2 (2.5–5 µM) for 24 h and then aliquots of PC3 cells (20×10<sup>3</sup>) were transferred in the upper compartment of the chamber. Cells migrated through the Matrigel on the filters of Boyden chambers were counted after 6 h and expressed as the absolute cell number ± SD; five different microscopic fields (magnification: x200) for each condition were examined and significant difference among specimens was established at <i>P</i>≤0.05.</p>", "links"=>[], "tags"=>["motility", "pc3"], "article_id"=>644335, "categories"=>["Chemistry", "Cancer", "Cell Biology"], "users"=>["Anna Laurenzana", "Manjola Balliu", "Cristina Cellai", "Maria Novella Romanelli", "Francesco Paoletti"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0058267.g006", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_S_2_reduces_invasiveness_migration_and_motility_potential_of_PC3_cells_/644335", "title"=>"(S)-2 reduces invasiveness, migration and motility potential of PC3 cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-03-05 10:38:29"}
  • {"files"=>["https://ndownloader.figshare.com/files/977000"], "description"=>"<p>(<b>A</b>) – Samples from PC3 and LNCaP cells treated without/with (S)-2 (2.5 and 5 µM) for 24 h were analysed by Western blot and immunodetected for: PARP and its cleaved fragment, γ-H2AX and acetyl-α-tubulin, while α-tubulin was used as loading control. (<b>B</b>) – Cells either untreated or treated with 2.5 µM (S)-2 for 48 h were incubated just 1 h prior to be harvested with FAM-DEVD-FMK carboxyfluoresceine and then rinsed twice with PBS and their green fluorescence was measured by flow cytometry (see comment of point B in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058267#pone-0058267-g002\" target=\"_blank\">Figure 2</a>). (<b>C</b>) – Microscopic evaluation of the effects of (S)-2 on the accumulation of neutral lipid droplets within PC3 cells treated for three days. After fixation, cells were stained with an ORO solution; quantification of ORO staining was carried out as described in Materials and Methods.</p>", "links"=>[], "tags"=>["lncap", "cells", "drug-induced"], "article_id"=>644331, "categories"=>["Chemistry", "Cancer", "Cell Biology"], "users"=>["Anna Laurenzana", "Manjola Balliu", "Cristina Cellai", "Maria Novella Romanelli", "Francesco Paoletti"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0058267.g005", "stats"=>{"downloads"=>1, "page_views"=>29, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_PC3_are_less_sensitive_than_LNCAP_cells_to_drug_induced_apoptosis_/644331", "title"=>"PC3 are less sensitive than LNCAP cells to drug-induced apoptosis.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-03-05 10:37:51"}
  • {"files"=>["https://ndownloader.figshare.com/files/977008"], "description"=>"<div><p>Histone deacetylase inhibitors (HDACi) represent a promising class of epigenetic agents with anticancer properties. Here, we report that (S)-2, a novel hydroxamate-based HDACi, shown previously to be effective against acute myeloid leukemia cells, was also a potent inducer of apoptosis/differentiation in human prostate LNCaP and PC3 cancer cells. In LNCaP cells (S)-2 was capable of triggering H3/H4 histone acetylation, H2AX phosphorylation as a marker of DNA damage and producing G<sub>0</sub>/G<sub>1</sub> cell cycle arrest. Consistently, (S)-2 led to enhanced expression of both the protein and mRNA p21 levels in LNCaP cells but, contrary to SAHA, not in normal non-tumorigenic prostate PNT1A cells. Mechanistic studies demonstrated that (S)-2-induced apoptosis in LNCaP cells developed through the cleavage of pro-caspase 9 and 3 and of poly(ADP-ribose)-polymerase accompanied by the dose-dependent loss of mitochondrial membrane potential. Indeed, the addition of the pan-caspase inhibitor Z-VAD-fmk greatly reduced drug-mediated apoptosis while the antioxidant <i>N</i>-acetyl-cysteine was virtually ineffective. Importantly, preliminary data with nude mice xenografted with LNCaP cells showed that (S)-2 prompted a decrease in the tumor volume and an increase in H2AX phosphorylation within the cancer cells. Moreover, the highly metastatic prostate cancer PC3 cells were also sensitive to (S)-2 that: i) induced growth arrest and moderate apoptosis; ii) steered cells towards differentiation and neutral lipid accumulation; iii) reduced cell invasiveness potential by decreasing the amount of MMP-9 activity and up-regulating TIMP-1 expression; and iv) inhibited cell motility and migration through the Matrigel. Overall, (S)-2 has proven to be a powerful HDACi capable of inducing growth arrest, cell death and/or differentiation of LNCaP and PC3 prostate cancer cells and, due to its low toxicity and efficacy <i>in vivo</i>, might also be of clinical interest to support conventional prostate cancer therapy.</p> </div>", "links"=>[], "tags"=>["histone", "deacetylase", "inhibitor", "lncap", "pc3", "prostate", "cancer", "cells"], "article_id"=>644339, "categories"=>["Chemistry", "Cancer", "Cell Biology"], "users"=>["Anna Laurenzana", "Manjola Balliu", "Cristina Cellai", "Maria Novella Romanelli", "Francesco Paoletti"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0058267", "stats"=>{"downloads"=>7, "page_views"=>29, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Effectiveness_of_the_Histone_Deacetylase_Inhibitor_S_2_against_LNCaP_and_PC3_Human_Prostate_Cancer_Cells__/644339", "title"=>"Effectiveness of the Histone Deacetylase Inhibitor (S)-2 against LNCaP and PC3 Human Prostate Cancer Cells", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-03-05 10:39:17"}
  • {"files"=>["https://ndownloader.figshare.com/files/976986"], "description"=>"<p>(<b>A</b>) – Cells (10<sup>5</sup>) were seeded in 6-well plates and allowed to attach overnight. On the next day (S)-2 was added at the indicated concentrations (0–5 µM) and viable cells (trypan blu-negative) were counted with the aid of a Bürker chamber along the following three days. (<b>B</b>, top) – (S)-2 induced G<sub>0</sub>/G<sub>1</sub> cell cycle arrest and increased p21 expression. LNCaP cells (2×10<sup>5</sup>) were treated with 2.5 µM drug for 24 h, then were detached and aliquots of cell suspensions were incubated with a propidium iodide (PI) solution for 30 min and subsequently analyzed by flow cytometry (DNA amount, X-axis; total events, Y-axis). The percentage of cells in the different phases of the cell cycle was calculated by the ModFit program and shown in each panel. (<b>B</b>, middle) – Phase contrast pictures of companion cultures indicated that (S)-2 induced morphological changes and a marked decrease in cell density. (<b>B</b>, bottom) – Cells were treated with 2.5 µM drug for the indicated time points and p21 protein levels were monitored by immunoblotting; GAPDH was also examined to ensure equal loading of samples in each lane. (<b>C</b>) – LNCaP cell growth arrest was not strictly dependent on the continual presence of drug. Cells have been seeded in 6-well plates (10<sup>5</sup> cell/well) and allowed to attach overnight. The day after cultures were added without/with 2.5–5 µM (S)-2 for 3d and then replaced with drug-free medium for additional 3d and compared to cultures where the drug was steadily maintained up to 6d when viable cells were counted. Each bar represents the mean obtained from triplicate wells ± SD.</p>", "links"=>[], "tags"=>["induced", "lncap"], "article_id"=>644321, "categories"=>["Chemistry", "Cancer", "Cell Biology"], "users"=>["Anna Laurenzana", "Manjola Balliu", "Cristina Cellai", "Maria Novella Romanelli", "Francesco Paoletti"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0058267.g001", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_S_2_induced_growth_arrest_in_LNCAP_cells_/644321", "title"=>"(S)-2 induced growth arrest in LNCAP cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-03-05 10:34:54"}

PMC Usage Stats | Further Information

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Relative Metric

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