AZD1480 Blocks Growth and Tumorigenesis of RET- Activated Thyroid Cancer Cell Lines
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{"title"=>"AZD1480 Blocks Growth and Tumorigenesis of RET- Activated Thyroid Cancer Cell Lines", "type"=>"journal", "authors"=>[{"first_name"=>"Joana P.", "last_name"=>"Couto", "scopus_author_id"=>"24780418300"}, {"first_name"=>"Ana", "last_name"=>"Almeida", "scopus_author_id"=>"35755545300"}, {"first_name"=>"Laura", "last_name"=>"Daly", "scopus_author_id"=>"55372085100"}, {"first_name"=>"Manuel", "last_name"=>"Sobrinho-Simões", "scopus_author_id"=>"7101632183"}, {"first_name"=>"Jacqueline F.", "last_name"=>"Bromberg", "scopus_author_id"=>"7103152598"}, {"first_name"=>"Paula", "last_name"=>"Soares", "scopus_author_id"=>"35478020200"}], "year"=>2012, "source"=>"PLoS ONE", "identifiers"=>{"pui"=>"365767501", "pmid"=>"23056499", "doi"=>"10.1371/journal.pone.0046869", "sgr"=>"84867019039", "issn"=>"19326203", "scopus"=>"2-s2.0-84867019039"}, "id"=>"2c078c58-ee2c-3a88-b0c6-d675013d9738", "abstract"=>"Persistent RET activation is a frequent event in papillary thyroid carcinoma (PTC) and medullary thyroid carcinoma (MTC). In these cancers, RET activates the ERK/MAPK, the PI3K/AKT/mTOR and the JAK/STAT3 pathways. Here, we tested the efficacy of a JAK1/2- inhibitor, AZD1480, in the in vitro and in vivo growth of thyroid cancer cell lines expressing oncogenic RET. Thyroid cancer cell lines harboring RET/PTC1 (TPC-1), RET M918T (MZ-CRC1) and RET C634W (TT) alterations, as well as TPC-1 xenografts, were treated with JAK inhibitor, AZD1480. This inhibitor led to growth inhibition and/or apoptosis of the thyroid cancer cell lines in vitro, as well as to tumor regression of TPC-1 xenografts, where it efficiently blocked STAT3 activation in tumor and stromal cells. This inhibition was associated with decreased proliferation, decreased blood vessel density, coupled with increased necrosis. However, AZD1480 repressed the growth of STAT3- deficient TPC-1 cells in vitro and in vivo, demonstrating that its effects in this cell line were independent of STAT3 in the tumor cells. In all cell lines, the JAK inhibitor reduced phospho-Y1062 RET levels, and mTOR effector phospho-S6, while JAK1/2 downregulation by siRNA did not affect cell growth nor RET and S6 activation. In conclusion, AZD1480 effectively blocks proliferation and tumor growth of activated RET- thyroid cancer cell lines, likely through direct RET inhibition in cancer cells as well as by modulation of the microenvironment (e.g. via JAK/phospho-STAT3 inhibition in endothelial cells). Thus, AZD1480 should be considered as a therapeutic agent for the treatment of RET- activated thyroid cancers.", "link"=>"http://www.mendeley.com/research/azd1480-blocks-growth-tumorigenesis-ret-activated-thyroid-cancer-cell-lines", "reader_count"=>24, "reader_count_by_academic_status"=>{"Librarian"=>1, "Researcher"=>7, "Student > Ph. D. Student"=>6, "Student > Postgraduate"=>2, "Other"=>2, "Student > Master"=>2, "Student > Bachelor"=>2, "Professor"=>2}, "reader_count_by_user_role"=>{"Librarian"=>1, "Researcher"=>7, "Student > Ph. D. Student"=>6, "Student > Postgraduate"=>2, "Other"=>2, "Student > Master"=>2, "Student > Bachelor"=>2, "Professor"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>4, "Medicine and Dentistry"=>7, "Agricultural and Biological Sciences"=>10, "Chemistry"=>1, "Psychology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>7}, "Chemistry"=>{"Chemistry"=>1}, "Psychology"=>{"Psychology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>10}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>4}, "Unspecified"=>{"Unspecified"=>1}}, "reader_count_by_country"=>{"Portugal"=>1}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/566666"], "description"=>"<p>(A) TPC-1, MZ-CRC1, TT and a (B) PCCl3-RET/PTC3 doxycycline-inducible cell line were treated for 24 hours with AZD1480 (1 µM), AZD6244 (1 µM), or a combination of both drugs. Total cell protein extracts were probed with antibodies for the indicated effectors of the JAK/STAT3, ERK/MAPK and PI3K/AKT signaling pathways as well as for phospho-RET Y1062. In the lower panel of TPC-1, the DMSO (D) lane is non-contiguous to the AZD6444 (6244) lane, in the same gel. (C) TPC-1 xenografts' representative sections were probed for the activation of STAT3 (phospho-STAT3), ERK/MAPK (phospho-ERK1/2) and PI3K/AKT (phospho-S6) signaling pathways. Quantification is represented graphically (mean ± SE). *p<0.05; **p<0.001.</p>", "links"=>[], "tags"=>["induces", "sustained", "downregulation", "ret", "tyrosine", "phosphorylation", "pathway", "activation"], "article_id"=>237154, "categories"=>["Chemistry", "Biotechnology", "Biochemistry", "Cancer", "Pharmacology"], "users"=>["Joana P. Couto", "Ana Almeida", "Laura Daly", "Manuel Sobrinho-Simões", "Jacqueline F. Bromberg", "Paula Soares"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0046869.g005", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_AZD1480_induces_sustained_downregulation_of_RET_tyrosine_phosphorylation_and_PI3K_AKT_pathway_activation_in_vitro_and_in_vivo_/237154", "title"=>"AZD1480 induces sustained downregulation of RET tyrosine phosphorylation and PI3K/AKT pathway activation <i>in vitro</i> and <i>in vivo</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-10-02 01:59:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/566360"], "description"=>"<p>(A) TPC-1 cells (10<sup>6</sup>) were injected subcutaneously in the flanks of nude mice. Following tumor engraftment (∼0.5 cm<sup>3</sup>), mice were distributed into four groups (n = 5/group) with similar mean tumor volumes. Groups were treated with drug vehicle (untreated), AZD6244, at 25 mg/Kg, once a day, or AZD1480, at 30 mg/Kg, bi-daily. Tumor volumes were determined bi-weekly (mean ± SE). (B) AZD1480- and AZD6244- treated TPC-1 tumor sections were immunostained for phospho-STAT3 and phospho-ERK1/2 expression, respectively. Phospho-STAT3-positive stromal cells are outlined with a dotted-line (magnification: 400x). (C) JAK inhibitor decreases proliferation and vasculogenesis of TPC-1 xenografts. H&E staining of TPC-1 tumors treated with drug vehicle (control), AZD6244 or AZD1480. Representative tumor sections were stained for proliferation (Ki67), angiogenesis (Meca-32) and apoptosis (TUNEL) markers. Original magnification: 200x. Quantification is represented graphically. **p<0.001; ***p<0.0001.</p>", "links"=>[], "tags"=>["leads", "tpc-1", "xenograft"], "article_id"=>236852, "categories"=>["Chemistry", "Biotechnology", "Biochemistry", "Cancer", "Pharmacology"], "users"=>["Joana P. Couto", "Ana Almeida", "Laura Daly", "Manuel Sobrinho-Simões", "Jacqueline F. Bromberg", "Paula Soares"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0046869.g003", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_AZD1480_leads_to_TPC_1_xenograft_tumor_remission_/236852", "title"=>"AZD1480 leads to TPC-1 xenograft tumor remission.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-10-02 01:54:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/566513"], "description"=>"<p>(A) STAT3 was knockdown in TPC-1 cells by a short hairpin. Phospho-STAT3 and STAT3 downregulation were confirmed by western-blotting. (B) TPC-1 shSTAT3 cells were treated with DMSO or AZD1480 (1 µM) and growth inhibition was determined by the SRB assay. Results are mean ± SE of three independent experiments. (C) TPC-1 shSTAT3 cells were injected subcutaneously in both flanks of nude mice. When tumors reached ∼0.5 cm<sup>3</sup>, mice were equally distributed in two groups: one was the control group (vehicle) and the other was treated with AZD1480 at 30 mg/Kg, bi-daily. (C1) Tumor volume was measured at the indicated time points. Results represent mean ± SE. (C2) Representative H&E and phospho-STAT3 immunostaining of tumors sections from untreated (vehicle) or AZD1480- treated TPC-1 shSTAT3 tumors. Arrows indicate phospho-STAT3- positive murine stromal cells. Magnification: 200x. ***p<0.0001.</p>", "links"=>[], "tags"=>["inhibition", "tpc-1", "cells", "tumors", "azd1480", "activated", "phospho-stat3"], "article_id"=>236999, "categories"=>["Chemistry", "Biotechnology", "Biochemistry", "Cancer", "Pharmacology"], "users"=>["Joana P. Couto", "Ana Almeida", "Laura Daly", "Manuel Sobrinho-Simões", "Jacqueline F. Bromberg", "Paula Soares"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0046869.g004", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Growth_inhibition_of_TPC_1_cells_and_tumors_by_AZD1480_is_independent_of_activated_phospho_STAT3_Tyr705_/236999", "title"=>"Growth inhibition of TPC-1 cells and tumors by AZD1480 is independent of activated phospho-STAT3 Tyr705.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-10-02 01:56:39"}
  • {"files"=>["https://ndownloader.figshare.com/files/566191"], "description"=>"<p>(A) TPC-1, MZ-CRC1 and TT were treated with AZD1480 (1 µM; +) for 72 hours. Cells were subjected to cycle profile analysis by flow cytometry. Results are representative of three independent experiments (mean ± SE). (B) Cells were treated with AZD1480 (1 µM) for 48 hours and apoptotic cell death was determined by TUNEL. (C) AZD1480 induces p27 upregulation and cyclin D1 and BCL-2 downregulation in thyroid cancer cell lines. TPC-1, MZ-CRC1 and TT cell lines were treated with AZD1480 (1 µM) for 24 hours. Cell lysates were probed with the indicated primary antibodies, by western-blotting. *p<0.05; ***p<0.0001.</p>", "links"=>[], "tags"=>["induces", "g1", "blockage", "apoptosis", "thyroid", "cancer-", "derived"], "article_id"=>236680, "categories"=>["Chemistry", "Biotechnology", "Biochemistry", "Cancer", "Pharmacology"], "users"=>["Joana P. Couto", "Ana Almeida", "Laura Daly", "Manuel Sobrinho-Simões", "Jacqueline F. Bromberg", "Paula Soares"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0046869.g002", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_AZD1480_induces_G1_blockage_and_apoptosis_of_thyroid_cancer_derived_cell_lines_/236680", "title"=>"AZD1480 induces G1 blockage and apoptosis of thyroid cancer- derived cell lines.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-10-02 01:51:20"}
  • {"files"=>["https://ndownloader.figshare.com/files/299499", "https://ndownloader.figshare.com/files/299535", "https://ndownloader.figshare.com/files/299570"], "description"=>"<div><p>Persistent RET activation is a frequent event in papillary thyroid carcinoma (PTC) and medullary thyroid carcinoma (MTC). In these cancers, RET activates the ERK/MAPK, the PI3K/AKT/mTOR and the JAK/STAT3 pathways. Here, we tested the efficacy of a JAK1/2- inhibitor, AZD1480, in the <em>in vitro</em> and <em>in vivo</em> growth of thyroid cancer cell lines expressing oncogenic RET. Thyroid cancer cell lines harboring <em>RET</em>/PTC1 (TPC-1), <em>RET</em> M918T (MZ-CRC1) and <em>RET</em> C634W (TT) alterations, as well as TPC-1 xenografts, were treated with JAK inhibitor, AZD1480. This inhibitor led to growth inhibition and/or apoptosis of the thyroid cancer cell lines <em>in vitro</em>, as well as to tumor regression of TPC-1 xenografts, where it efficiently blocked STAT3 activation in tumor and stromal cells. This inhibition was associated with decreased proliferation, decreased blood vessel density, coupled with increased necrosis. However, AZD1480 repressed the growth of STAT3- deficient TPC-1 cells <em>in vitro</em> and <em>in vivo</em>, demonstrating that its effects in this cell line were independent of STAT3 in the tumor cells. In all cell lines, the JAK inhibitor reduced phospho-Y1062 RET levels, and mTOR effector phospho-S6, while JAK1/2 downregulation by siRNA did not affect cell growth nor RET and S6 activation. In conclusion, AZD1480 effectively blocks proliferation and tumor growth of activated RET- thyroid cancer cell lines, likely through direct RET inhibition in cancer cells as well as by modulation of the microenvironment (e.g. via JAK/phospho-STAT3 inhibition in endothelial cells). Thus, AZD1480 should be considered as a therapeutic agent for the treatment of RET- activated thyroid cancers.</p> </div>", "links"=>[], "tags"=>["azd1480", "blocks", "tumorigenesis", "ret-", "activated", "thyroid", "cancer", "lines"], "article_id"=>119049, "categories"=>["Chemistry", "Biotechnology", "Biochemistry", "Cancer", "Pharmacology"], "users"=>["Joana P. Couto", "Ana Almeida", "Laura Daly", "Manuel Sobrinho-Simões", "Jacqueline F. Bromberg", "Paula Soares"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0046869.s001", "https://dx.doi.org/10.1371/journal.pone.0046869.s002", "https://dx.doi.org/10.1371/journal.pone.0046869.s003"], "stats"=>{"downloads"=>3, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/AZD1480_Blocks_Growth_and_Tumorigenesis_of_RET_Activated_Thyroid_Cancer_Cell_Lines/119049", "title"=>"AZD1480 Blocks Growth and Tumorigenesis of RET- Activated Thyroid Cancer Cell Lines", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-10-02 02:30:49"}
  • {"files"=>["https://ndownloader.figshare.com/files/566805"], "description"=>"<p>(A) The expression of JAK1 or/and JAK2 was downregulated by siRNA in TPC-1, MZ-CRC1 and TT cell lines. The levels of the indicated proteins and their phosphorylation status were determined after 48 hours, by western-blot analysis. (B) Cell proliferation was measured by BrdU incorporation, 48 hours after transfection with a combination of siRNAs targeting both JAK1 and JAK2. Results represent mean ± SE of three independent experiments. *p<0.05.</p>", "links"=>[], "tags"=>["knockdown", "sirna", "proliferation", "ret", "PI3K", "pathway", "activation", "thyroid", "cancer"], "article_id"=>237291, "categories"=>["Chemistry", "Biotechnology", "Biochemistry", "Cancer", "Pharmacology"], "users"=>["Joana P. Couto", "Ana Almeida", "Laura Daly", "Manuel Sobrinho-Simões", "Jacqueline F. Bromberg", "Paula Soares"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0046869.g006", "stats"=>{"downloads"=>0, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_JAK1_2_knockdown_by_siRNA_does_not_affect_proliferation_nor_RET_and_PI3K_pathway_activation_in_thyroid_cancer_cell_lines_/237291", "title"=>"JAK1/2 knockdown by siRNA does not affect proliferation nor RET and PI3K pathway activation in thyroid cancer cell lines.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-10-02 02:01:31"}
  • {"files"=>["https://ndownloader.figshare.com/files/566043"], "description"=>"<p>(A) TPC-1, MZ-CRC1 and TT cell lines were treated with AZD6244 (1 µM), AZD1480 (1 µM), and a combination of both drugs (1 µM each) for the indicated time. A rat- derived non malignant thyroid cell line, PCCl3, was treated with AZD1480 (1 µM) or control DMSO. Growth was determined by the sulphorhodamine B assay. (B) Cell lines were treated for 48 or 72 hours with different concentrations of AZD1480 (0.1, 0.5 and 1 µM) and cell density was determined. Data are shown as mean ± SE of three independent experiments. ***p<0.0001.</p>", "links"=>[], "tags"=>["inhibits", "ret-activated", "thyroid", "cancer-", "derived"], "article_id"=>236526, "categories"=>["Chemistry", "Biotechnology", "Biochemistry", "Cancer", "Pharmacology"], "users"=>["Joana P. Couto", "Ana Almeida", "Laura Daly", "Manuel Sobrinho-Simões", "Jacqueline F. Bromberg", "Paula Soares"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0046869.g001", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_AZD1480_inhibits_the_growth_of_RET_activated_thyroid_cancer_derived_cell_lines_/236526", "title"=>"AZD1480 inhibits the growth of RET-activated thyroid cancer- derived cell lines.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-10-02 01:48:46"}

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  • {"unique-ip"=>"1", "full-text"=>"1", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"9"}
  • {"unique-ip"=>"7", "full-text"=>"6", "pdf"=>"5", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"6", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2017", "month"=>"10"}

Relative Metric

{"start_date"=>"2012-01-01T00:00:00Z", "end_date"=>"2012-12-31T00:00:00Z", "subject_areas"=>[{"subject_area"=>"/Biology and life sciences/Cell biology", "average_usage"=>[319, 556, 679, 785, 881, 970, 1062, 1149, 1236, 1323, 1402, 1474, 1545, 1617, 1681, 1754, 1822, 1892, 1963, 2031, 2099, 2165, 2233, 2299, 2359]}, {"subject_area"=>"/Medicine and health sciences/Oncology", "average_usage"=>[301, 551, 686, 790, 883, 972, 1069, 1162, 1250, 1341, 1426, 1503, 1571, 1634, 1701, 1779, 1848, 1919, 1986, 2052, 2114, 2183, 2253, 2301, 2367]}, {"subject_area"=>"/Medicine and health sciences/Pharmaceutics", "average_usage"=>[305, 566, 705, 814, 911, 1028, 1121, 1228, 1325, 1435, 1532, 1608, 1690, 1769, 1843, 1921, 1997, 2089, 2155, 2225, 2285, 2361, 2433, 2496, 2560]}]}
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