Therapeutic Potential of the Translation Inhibitor Silvestrol in Hepatocellular Cancer
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{"title"=>"Therapeutic Potential of the Translation Inhibitor Silvestrol in Hepatocellular Cancer", "type"=>"journal", "authors"=>[{"first_name"=>"Takayuki", "last_name"=>"Kogure", "scopus_author_id"=>"7102320812"}, {"first_name"=>"A. Douglas", "last_name"=>"Kinghorn", "scopus_author_id"=>"7103350857"}, {"first_name"=>"Irene", "last_name"=>"Yan", "scopus_author_id"=>"26327196800"}, {"first_name"=>"Brad", "last_name"=>"Bolon", "scopus_author_id"=>"7003438991"}, {"first_name"=>"David M.", "last_name"=>"Lucas", "scopus_author_id"=>"7202026135"}, {"first_name"=>"Michael R.", "last_name"=>"Grever", "scopus_author_id"=>"7005254341"}, {"first_name"=>"Tushar", "last_name"=>"Patel", "scopus_author_id"=>"55630340500"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "pui"=>"369899230", "sgr"=>"84884645790", "doi"=>"10.1371/journal.pone.0076136", "scopus"=>"2-s2.0-84884645790", "pmid"=>"24086701"}, "id"=>"87339479-e2ba-3134-a087-0a223b2d0e66", "abstract"=>"BACKGROUND & AIMS: Although hepatocellular cancers (HCC) frequently arise in the setting of fibrosis and a hepatic regenerative response requiring new cell growth, therapeutic strategies for these cancers have not targeted protein synthesis. Silvestrol, a rocaglate isolated from Aglaiafoveolata, can inhibit protein synthesis by modulating the initiation of translation through the eukaryotic initiation factor 4A. In this study, we evaluated the therapeutic efficacy of silvestrol for HCC.\\n\\nMETHODS: The efficacy of silvestrol was examined using human HCC cells in vitro using an orthotopic tumor cell xenograft model in a fibrotic liver. The impact of silvestrol on the liver was assessed in vivo in wild-type mice.\\n\\nRESULTS: Silvestrol inhibited cell growth with an IC50 of 12.5-86 nM in four different HCC cell lines. In vitro, silvestrol increased apoptosis and caspase 3/7 activity accompanied by loss of mitochondrial membrane potential and decreased expression of Mcl-1 and Bcl-xL. A synergistic effect was observed when silvestrol was combined with other therapeutic agents, with a dose-reduction index of 3.42-fold with sorafenib and 1.75-fold with rapamycin at a fractional effect of 0.5. In vivo, an antitumor effect was observed with 0.4 mg/kg silvestrol compared to controls after one week, and survival of tumor-bearing mice was improved with a median survival time of 42 and 28 days in the silvestrol and control groups, respectively. The effect on survival was not observed in orthotopic xenografts in non-fibrotic livers. Silvestrol treatment in vivo did not alter liver structure.\\n\\nCONCLUSIONS: These data identify silvestrol as a novel, structurally unique drug with potent anticancer activity for HCC and support the potential value of targeting initiation of translation in the treatment of HCC.", "link"=>"http://www.mendeley.com/research/therapeutic-potential-translation-inhibitor-silvestrol-hepatocellular-cancer", "reader_count"=>20, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>1, "Researcher"=>3, "Student > Ph. D. Student"=>7, "Student > Master"=>4, "Other"=>1, "Student > Bachelor"=>3}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>1, "Researcher"=>3, "Student > Ph. D. Student"=>7, "Student > Master"=>4, "Other"=>1, "Student > Bachelor"=>3}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Agricultural and Biological Sciences"=>10, "Medicine and Dentistry"=>2, "Arts and Humanities"=>1, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Chemistry"=>3, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>2}, "Chemistry"=>{"Chemistry"=>3}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>10}, "Unspecified"=>{"Unspecified"=>2}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}, "Arts and Humanities"=>{"Arts and Humanities"=>1}}, "reader_count_by_country"=>{"Malaysia"=>1}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1216604"], "description"=>"<p>A. Treatment protocol. B. Luminescence (% of baseline) at one week after the treatment in each group (mean ± SE) are shown. *, <i>p</i> < 0.05. C. Response rate in each treatment group is shown. The percentage of mice with a response defined as reduction in bioluminescence of >30% is shown. D. Survival curves of each treatment group by Kaplan-Meier method are shown. * control vs. high dose p=0.037. ** control vs. low dose, p=0.024.</p>", "links"=>[], "tags"=>["silvestrol", "orthotopic", "hcc", "xenografts", "nude"], "article_id"=>808800, "categories"=>["Biological Sciences"], "users"=>["Takayuki Kogure", "A. Douglas Kinghorn", "Irene Yan", "Brad Bolon", "David M. Lucas", "Michael R. Grever", "Tushar Patel"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0076136.g009", "stats"=>{"downloads"=>2, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Anti_tumor_effect_of_silvestrol_in_orthotopic_human_HCC_xenografts_in_nude_mice_/808800", "title"=>"Anti-tumor effect of silvestrol in orthotopic human HCC xenografts in nude mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-09-26 01:47:04"}
  • {"files"=>["https://ndownloader.figshare.com/files/1216593"], "description"=>"<p>Human HCC cells were seeded onto 96-well plates (5,000 cells/well) and incubated with various concentrations of silvestrol or control (diluent). Cell viability was assessed after 72 hours using a metabolic live cell assay (CellTiter 96 AQ, Promega Corp., Madison, WI). The data represents the mean and SD of five separate determinations.</p>", "links"=>[], "tags"=>["silvestrol", "hcc"], "article_id"=>808789, "categories"=>["Biological Sciences"], "users"=>["Takayuki Kogure", "A. Douglas Kinghorn", "Irene Yan", "Brad Bolon", "David M. Lucas", "Michael R. Grever", "Tushar Patel"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0076136.g001", "stats"=>{"downloads"=>2, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cytotoxicity_of_silvestrol_on_HCC_cells_/808789", "title"=>"Cytotoxicity of silvestrol on HCC cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-09-26 01:47:04"}
  • {"files"=>["https://ndownloader.figshare.com/files/1216594"], "description"=>"<p>PLC/PRF/5 HCC cells were seeded onto 4-well chamber slide (25,000 cells/well) and were incubated with 100 nM silvestrol for 24 hours. Apoptotic cells were detected by fluorescence microscopy after DAPI staining. The proportion of cells showing morphological features of apoptosis were counted. *, <i>p</i> < 0.05, t-test.</p>", "links"=>[], "tags"=>["apoptosis"], "article_id"=>808790, "categories"=>["Biological Sciences"], "users"=>["Takayuki Kogure", "A. Douglas Kinghorn", "Irene Yan", "Brad Bolon", "David M. Lucas", "Michael R. Grever", "Tushar Patel"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0076136.g002", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Induction_of_cell_apoptosis_by_silvestrol_/808790", "title"=>"Induction of cell apoptosis by silvestrol.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-09-26 01:47:04"}
  • {"files"=>["https://ndownloader.figshare.com/files/1216596"], "description"=>"<p>(A) PLC/PRF/5 HCC cells were seeded on 96-well plate (5,000 cells/well) and incubated with 100 nM silvestrol for up to 24 hours. Caspase-3/7 activation was assessed using a luminometric assay (Caspase-Glo 3/7 Assay, Promega Corp., Madison WI). The data represents the mean and SD of three separate determinations. (B) PLC/PRF/5 cells were seeded on 6-well plates (20,000 cells/well) and incubated with 100 nM silvestrol (100 nM) for up to 24 hours. Cells were harvested at the indicated times, and immunoblot analysis for apoptosis-related proteins was performed. *, <i>p</i> < 0.05, ANOVA, Fisher’s PLSD (C) PLC/PRF/5 cells and HepG2 cells were seeded on 6-well plates and incubated with 100 nM silvestrol for up to 24 hours. Expression of Mcl-1 protein was assessed by immunoblotting. (D) RNA was extracted at each time point and Mcl-1 mRNA expression level was assessed by quantitative real-time PCR. Values are expressed relative to expression in no-treatment control after normalization using GAPDH as an internal control. The data represents the mean and SD. *, <i>p</i> < 0.05, ANOVA, Fisher’s PLSD.</p>", "links"=>[], "tags"=>["apoptosis-related", "proteins"], "article_id"=>808792, "categories"=>["Biological Sciences"], "users"=>["Takayuki Kogure", "A. Douglas Kinghorn", "Irene Yan", "Brad Bolon", "David M. Lucas", "Michael R. Grever", "Tushar Patel"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0076136.g003", "stats"=>{"downloads"=>0, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Modulation_of_expression_of_apoptosis_related_proteins_by_silvestrol_/808792", "title"=>"Modulation of expression of apoptosis-related proteins by silvestrol.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-09-26 01:47:04"}
  • {"files"=>["https://ndownloader.figshare.com/files/1216597"], "description"=>"<p>A, PLC/PRF/5 cells were seeded on 4-well chamber slide (25,000 cells/well) and incubated with 100 nM silvestrol for 24 hours. Cells were stained with JC-1 and mitochondrial permeability was detected using fluorescence microscopy. Cells exhibit red fluorescence under basal conditions, but green fluorescence following alteration in mitochondrial membrane potential. B, PLC/PRF/5 cells were seeded on 96-well plate (5000 cells/well) and incubated with 100 nM silvestrol for 24 hours. Cells were stained with JC-1 and the ratio of green to red fluorescence was determined fluorometrically (mean ± SD). *, <i>p</i> < 0.05, t-test.</p>", "links"=>[], "tags"=>["mitochondrial", "membrane"], "article_id"=>808793, "categories"=>["Biological Sciences"], "users"=>["Takayuki Kogure", "A. Douglas Kinghorn", "Irene Yan", "Brad Bolon", "David M. Lucas", "Michael R. Grever", "Tushar Patel"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0076136.g004", "stats"=>{"downloads"=>0, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Decrease_of_mitochondrial_membrane_potential_by_silvestrol_/808793", "title"=>"Decrease of mitochondrial membrane potential by silvestrol.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-09-26 01:47:04"}
  • {"files"=>["https://ndownloader.figshare.com/files/1216598"], "description"=>"<p>PLC/PRF/5 cells were seeded on 96-well plates (5000 cells/well) and were incubated for 72 hours with various concentrations of silvestrol (SVL) and (A) sorafenib (SRF) at a fixed ratio of SVL:SRF of 1:250 or (B) rapamycin (RPM) at a fixed ratio of SVL:RPM of 1:2.5. Cell viability was assessed using a metabolic assay (CellTiter 96 AQ, Promega Corp., Madison, WI). Potential interactions between silvestrol and sorafenib or rapamycin were evaluated using the median effects analysis of Chou and Talalay to derive the (C) combination index and (D) dose-reduction index of the combinations.</p>", "links"=>[], "tags"=>["silvestrol", "sorafenib", "rapamycin"], "article_id"=>808794, "categories"=>["Biological Sciences"], "users"=>["Takayuki Kogure", "A. Douglas Kinghorn", "Irene Yan", "Brad Bolon", "David M. Lucas", "Michael R. Grever", "Tushar Patel"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0076136.g005", "stats"=>{"downloads"=>5, "page_views"=>18, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Synergistic_effect_between_silvestrol_SVL_and_sorafenib_SRF_or_rapamycin_RPM_/808794", "title"=>"Synergistic effect between silvestrol (SVL) and sorafenib (SRF) or rapamycin (RPM).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-09-26 01:47:04"}
  • {"files"=>["https://ndownloader.figshare.com/files/1216599"], "description"=>"<p>Hepatic fibrosis was induced in nude mice by twice weekly injection of carbon tetrachloride (CCl<sub>4</sub>) at the dosage of 0.4 g/kg body weight for 6, 9, and 12 weeks. <i>A</i> and <i>B</i>, typical pictures of liver histopathology with trichrome staining (A, control; B, CCl4 12 weeks). The liver was fixed with formalin and stained with Masson’s trichome. <i>C</i>, At least five images were randomly captured from each liver section and the percentage of the area of fibrosis was analyzed using NIH ImageJ software. Data represent the percentage of total area with fibrosis expressed as mean ± SD. *, <i>p</i> < 0.05, ANOVA, Fisher’s PLSD.</p>", "links"=>[], "tags"=>["fibrosis", "carbon", "tetrachloride"], "article_id"=>808795, "categories"=>["Biological Sciences"], "users"=>["Takayuki Kogure", "A. Douglas Kinghorn", "Irene Yan", "Brad Bolon", "David M. Lucas", "Michael R. Grever", "Tushar Patel"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0076136.g006", "stats"=>{"downloads"=>2, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Induction_of_fibrosis_in_the_liver_by_carbon_tetrachloride_administration_/808795", "title"=>"Induction of fibrosis in the liver by carbon tetrachloride administration.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-09-26 01:47:04"}
  • {"files"=>["https://ndownloader.figshare.com/files/1216600"], "description"=>"<p><i>A</i>, <i>In </i><i>vitro</i> bioluminescence imaging of PLC-<i>luc</i> cells. Cells were counted and seeded on black 96-well plates. D-luciferin (150 µg/ml) was added to each well and imaging was performed using IVIS. Bioluminescence is plotted against cell number. <i>B</i>, <i>In </i><i>vivo</i> bioluminescence imaging. Orthotopic tumors were established by direct intra-hepatic injection of PLC-<i>luc</i> cells. One million PLC-<i>luc</i> cells were injected into the left lobe of the liver. The growth of tumors were monitored by bioluminescent imaging using the IVIS. C, The relation between the tumor volume and bioluminescence. After at least 4 weeks of monitoring mice were sacrificed and liver tumor volumes were obtained using caliper measurement. The estimated volume of tumor after excision is plotted against bioluminescence determined in situ.</p>", "links"=>[], "tags"=>[], "article_id"=>808796, "categories"=>["Biological Sciences"], "users"=>["Takayuki Kogure", "A. Douglas Kinghorn", "Irene Yan", "Brad Bolon", "David M. Lucas", "Michael R. Grever", "Tushar Patel"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0076136.g007", "stats"=>{"downloads"=>0, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Estimation_of_tumor_growth_by_bioluminescence_/808796", "title"=>"Estimation of tumor growth by bioluminescence.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-09-26 01:47:04"}
  • {"files"=>["https://ndownloader.figshare.com/files/1216603"], "description"=>"<p>Mice received 0.4 g/kg carbon tetrachloride to induce liver fibrosis (n=19) or vehicle injections (n=18) for ten weeks. Orthotopic tumors were then established by direct intra-hepatic injection of 10<sup>6</sup> PLC-<i>luc</i> cells. Tumor cell xenograft growth was monitored by bioluminescence imaging and was detected in 18 mice with fibrotic livers and in 15 mice without liver fibrosis. (A) The time in days (mean ± SE) for liver tumor growth from tumor cell injection to bioluminescence intensity of 10<sup>7</sup> photon/sec is shown. (B) Frequency of failure of tumor formation (%). (C) Effect of fibrosis on tumor growth. The change in bioluminescence intensity as a percent of baseline (mean ± SE) is plotted against time. Once bioluminescence exceeded 10<sup>7</sup> photon/sec, each mouse was randomized to a treatment arm and receive silvestrol or diluent (control). D, Survival curve of <i>control</i> group. The presence of liver fibrosis did not affect the survival of mice with tumor xenografts that did not receive any treatment. *, <i>p</i> < 0.05.</p>", "links"=>[], "tags"=>["fibrosis", "initiation"], "article_id"=>808799, "categories"=>["Biological Sciences"], "users"=>["Takayuki Kogure", "A. Douglas Kinghorn", "Irene Yan", "Brad Bolon", "David M. Lucas", "Michael R. Grever", "Tushar Patel"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0076136.g008", "stats"=>{"downloads"=>5, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_liver_fibrosis_on_tumor_initiation_and_growth_/808799", "title"=>"Effect of liver fibrosis on tumor initiation and growth.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-09-26 01:47:04"}

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  • {"unique-ip"=>"14", "full-text"=>"19", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"7"}
  • {"unique-ip"=>"9", "full-text"=>"9", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"5"}
  • {"unique-ip"=>"11", "full-text"=>"13", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"8"}
  • {"unique-ip"=>"9", "full-text"=>"8", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"9"}
  • {"unique-ip"=>"7", "full-text"=>"7", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"2"}
  • {"unique-ip"=>"8", "full-text"=>"9", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"3"}
  • {"unique-ip"=>"9", "full-text"=>"15", "pdf"=>"8", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"12", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"4"}
  • {"unique-ip"=>"13", "full-text"=>"17", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"5"}

Relative Metric

{"start_date"=>"2013-01-01T00:00:00Z", "end_date"=>"2013-12-31T00:00:00Z", "subject_areas"=>[{"subject_area"=>"/Biology and life sciences/Cell biology", "average_usage"=>[272, 472, 600, 713, 815, 911, 1004, 1094, 1185, 1273, 1358, 1441]}, {"subject_area"=>"/Biology and life sciences/Genetics", "average_usage"=>[284, 491, 620, 738, 843, 945, 1043, 1137, 1225, 1315, 1400, 1479, 1555]}, {"subject_area"=>"/Medicine and health sciences/Oncology", "average_usage"=>[249, 468, 599, 718, 820, 920, 1008, 1093, 1181, 1281, 1357, 1444, 1517]}, {"subject_area"=>"/Physical sciences", "average_usage"=>[254, 431, 547, 651, 748, 842, 932, 1017, 1098, 1178, 1259, 1336, 1404]}, {"subject_area"=>"/Physical sciences/Physics", "average_usage"=>[254, 421, 527, 626, 720, 813, 900, 983, 1063, 1136, 1210, 1283, 1342]}]}
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