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<!DOCTYPE html> <html lang="en" dir="ltr" xmlns="http://www.w3.org/1999/xhtml" xmlns:mml="http://www.w3.org/1998/Math/MathML"> <head prefix="og: http://ogp.me/ns# article: http://ogp.me/ns/article# book: http://ogp.me/ns/book#" >  <link rel="dns-prefetch" href="//cdn.foxycart.com" /> <link rel="dns-prefetch" href="//scholar.google.com" /> <meta http-equiv="Content-Type" content="text/html; charset=utf-8" /> <meta name="Generator" content="Drupal 7 (http://drupal.org)" /> <link rel="canonical" href="https://ar.iiarjournals.org/content/39/11/5973" /> <link rel="alternate" type="application/pdf" title="Full Text (PDF)" href="/content/39/11/5973.full.pdf" /> <link rel="alternate" type="text/plain" title="Full Text (Plain)" href="/content/39/11/5973.full.txt" /> <link rel="alternate" type="application/vnd.ms-powerpoint" title="Powerpoint" href="/content/39/11/5973.ppt" /> <meta name="issue_cover_image" content="https://ar.iiarjournals.org/sites/default/files/highwire/default/covers/acr_default_cover_0.gif" /> <meta name="type" content="article" /> <meta name="category" content="research-article" /> <meta name="HW.identifier" content="/anticanres/39/11/5973.atom" /> <meta name="HW.pisa" content="anticanres;39/11/5973" /> <meta name="DC.Format" content="text/html" /> <meta name="DC.Language" content="en" /> <meta name="DC.Title" content="Antiproliferative Effect of Lenvatinib on Human Liver Cancer Cell Lines In Vitro and In Vivo" /> <meta name="DC.Identifier" content="10.21873/anticanres.13802" /> <meta name="DC.Date" content="2019-11-01" /> <meta name="DC.Publisher" content="International Institute of Anticancer Research" /> <meta name="DC.Rights" content="Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved" /> <meta name="DC.AccessRights" content="restricted" /> <meta name="DC.Description" content="Background/Aim: Lenvatinib is a potent inhibitor of receptor tyrosine kinases, targeting vascular endothelial growth factor receptors (VEGFR1-3), fibroblast growth factor receptors (FGFR1-4), KIT, and RET. Here, we investigated the antiproliferative effects of lenvatinib in liver cancer cells in vitro and in vivo. Materials and Methods: Eleven hepatocellular carcinoma cell lines and two combined hepatocellular/cholangiocarcinoma cell lines were treated with 0-30 μM lenvatinib. Cell growth, apoptosis and the expression of FGFR1-4, FGF19, fibroblast growth factor receptor substrate (FRS)2α and RET were examined. Two HCC cell lines were subcutaneously implanted on nude mice and mice were treated with 3, 10, 30 mg/kg/day of lenvatinib or vehicle for 14 consecutive days. Tumor volume was measured every 3 days. Mice were sacrificed on day 15 and tumors were processed for histological examination. Blood vessels, microvessel density, necrosis, and apoptosis were also examined. Results: Lenvatinib dose- and time-dependently inhibited growth of all cell lines; however, sensitivity to lenvatinib varied. Apoptosis was not observed in any cell line, and expression of FGFR1, -2, -3 and -4, FGF19, FRS2α, and RET were observed in these cell lines. Cell lines with high expression of these factors showed higher response to lenvatinib. In mice, lenvatinib dose-dependently suppressed tumor growth. Blood vessels and microvessel density were significantly reduced and the rate of necrosis was significantly increased by lenvatinib; apoptosis was not observed. Conclusion: Antiproliferative effects of lenvatinib on liver cancer cells were observed in vitro and in vivo. Lenvatinib may suppress tumor formation by inhibiting angiogenesis, and via an additional direct antiproliferative effect in some liver cancer cells." /> <meta name="DC.Contributor" content="SACHIKO OGASAWARA" /> <meta name="DC.Contributor" content="YUTARO MIHARA" /> <meta name="DC.Contributor" content="REIICHIRO KONDO" /> <meta name="DC.Contributor" content="HIRONORI KUSANO" /> <meta name="DC.Contributor" content="JUN AKIBA" /> <meta name="DC.Contributor" content="HIROHISA YANO" /> <meta name="article:published_time" content="2019-11-01" /> <meta name="article:section" content="Experimental Studies" /> <meta name="citation_title" content="Antiproliferative Effect of Lenvatinib on Human Liver Cancer Cell Lines In Vitro and In Vivo" /> <meta name="citation_abstract" lang="en" content="<p>Background/Aim: Lenvatinib is a potent inhibitor of receptor tyrosine kinases, targeting vascular endothelial growth factor receptors (VEGFR1-3), fibroblast growth factor receptors (FGFR1-4), KIT, and RET. Here, we investigated the antiproliferative effects of lenvatinib in liver cancer cells in vitro and in vivo. Materials and Methods: Eleven hepatocellular carcinoma cell lines and two combined hepatocellular/cholangiocarcinoma cell lines were treated with 0-30 μM lenvatinib. Cell growth, apoptosis and the expression of FGFR1-4, FGF19, fibroblast growth factor receptor substrate (FRS)2α and RET were examined. Two HCC cell lines were subcutaneously implanted on nude mice and mice were treated with 3, 10, 30 mg/kg/day of lenvatinib or vehicle for 14 consecutive days. Tumor volume was measured every 3 days. Mice were sacrificed on day 15 and tumors were processed for histological examination. Blood vessels, microvessel density, necrosis, and apoptosis were also examined. Results: Lenvatinib dose- and time-dependently inhibited growth of all cell lines; however, sensitivity to lenvatinib varied. Apoptosis was not observed in any cell line, and expression of FGFR1, -2, -3 and -4, FGF19, FRS2α, and RET were observed in these cell lines. Cell lines with high expression of these factors showed higher response to lenvatinib. In mice, lenvatinib dose-dependently suppressed tumor growth. Blood vessels and microvessel density were significantly reduced and the rate of necrosis was significantly increased by lenvatinib; apoptosis was not observed. Conclusion: Antiproliferative effects of lenvatinib on liver cancer cells were observed in vitro and in vivo. Lenvatinib may suppress tumor formation by inhibiting angiogenesis, and via an additional direct antiproliferative effect in some liver cancer cells.</p>" /> <meta name="citation_journal_title" content="Anticancer Research" /> <meta name="citation_publisher" content="International Institute of Anticancer Research" /> <meta name="citation_publication_date" content="2019/11/01" /> <meta name="citation_mjid" content="anticanres;39/11/5973" /> <meta name="citation_id" content="39/11/5973" /> <meta name="citation_public_url" content="https://ar.iiarjournals.org/content/39/11/5973" /> <meta name="citation_abstract_html_url" content="https://ar.iiarjournals.org/content/39/11/5973.abstract" /> <meta name="citation_full_html_url" content="https://ar.iiarjournals.org/content/39/11/5973.full" /> <meta name="citation_pdf_url" content="https://ar.iiarjournals.org/content/anticanres/39/11/5973.full.pdf" /> <meta name="citation_issn" content="0250-7005" /> <meta name="citation_issn" content="1791-7530" /> <meta name="citation_doi" content="10.21873/anticanres.13802" /> <meta name="citation_pmid" content="31704822" /> <meta name="citation_volume" content="39" /> <meta name="citation_issue" content="11" /> <meta name="citation_article_type" content="Research Article" /> <meta name="citation_section" content="Experimental Studies" /> <meta name="citation_firstpage" content="5973" /> <meta name="citation_lastpage" content="5982" /> <meta name="citation_author" content="SACHIKO OGASAWARA" /> <meta name="citation_author_institution" content="Department of Pathology, Kurume University School of Medicine, Kurume, Japan" /> <meta name="citation_author_email" content="sachiko@med.kurume-u.ac.jp" /> <meta name="citation_author" content="YUTARO MIHARA" /> <meta name="citation_author_institution" content="Department of Pathology, Kurume University School of Medicine, Kurume, Japan" /> <meta name="citation_author" content="REIICHIRO KONDO" /> <meta name="citation_author_institution" content="Department of Pathology, Kurume University School of Medicine, Kurume, Japan" /> <meta name="citation_author" content="HIRONORI KUSANO" /> <meta name="citation_author_institution" content="Department of Pathology, Kurume University School of Medicine, Kurume, Japan" /> <meta name="citation_author" content="JUN AKIBA" /> <meta name="citation_author_institution" content="Department of Diagnostic Pathology, Kurume University Hospital, Kurume, Japan" /> <meta name="citation_author" content="HIROHISA YANO" /> <meta name="citation_author_institution" content="Department of Pathology, Kurume University School of Medicine, Kurume, Japan" /> <meta name="citation_reference" content="citation_journal_title=Int J Cancer;citation_author=J. 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Patel;citation_author=CJ. Ren;citation_author=A. Gualandris;citation_author=G. Pintucci;citation_author=ES. Robbins;citation_author=RL. Shapiro;citation_author=AC. Galloway;citation_author=DB. Rifkin;citation_author=P. 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Here, we investigated the antiproliferative effects of lenvatinib in liver cancer cells in vitro and in vivo. Materials and Methods: Eleven hepatocellular carcinoma cell lines and two combined hepatocellular/cholangiocarcinoma cell lines were treated with 0-30 μM lenvatinib. Cell growth, apoptosis and the expression of FGFR1-4, FGF19, fibroblast growth factor receptor substrate (FRS)2α and RET were examined. Two HCC cell lines were subcutaneously implanted on nude mice and mice were treated with 3, 10, 30 mg/kg/day of lenvatinib or vehicle for 14 consecutive days. Tumor volume was measured every 3 days. Mice were sacrificed on day 15 and tumors were processed for histological examination. Blood vessels, microvessel density, necrosis, and apoptosis were also examined. Results: Lenvatinib dose- and time-dependently inhibited growth of all cell lines; however, sensitivity to lenvatinib varied. Apoptosis was not observed in any cell line, and expression of FGFR1, -2, -3 and -4, FGF19, FRS2α, and RET were observed in these cell lines. Cell lines with high expression of these factors showed higher response to lenvatinib. In mice, lenvatinib dose-dependently suppressed tumor growth. Blood vessels and microvessel density were significantly reduced and the rate of necrosis was significantly increased by lenvatinib; apoptosis was not observed. Conclusion: Antiproliferative effects of lenvatinib on liver cancer cells were observed in vitro and in vivo. Lenvatinib may suppress tumor formation by inhibiting angiogenesis, and via an additional direct antiproliferative effect in some liver cancer cells." /> <meta name="og-title" property="og:title" content="Antiproliferative Effect of Lenvatinib on Human Liver Cancer Cell Lines In Vitro and In Vivo" /> <meta name="og-url" property="og:url" content="https://ar.iiarjournals.org/content/39/11/5973" /> <meta name="og-site-name" property="og:site_name" content="Anticancer Research" /> <meta name="og-description" property="og:description" content="Background/Aim: Lenvatinib is a potent inhibitor of receptor tyrosine kinases, targeting vascular endothelial growth factor receptors (VEGFR1-3), fibroblast growth factor receptors (FGFR1-4), KIT, and RET. Here, we investigated the antiproliferative effects of lenvatinib in liver cancer cells in vitro and in vivo. Materials and Methods: Eleven hepatocellular carcinoma cell lines and two combined hepatocellular/cholangiocarcinoma cell lines were treated with 0-30 μM lenvatinib. Cell growth, apoptosis and the expression of FGFR1-4, FGF19, fibroblast growth factor receptor substrate (FRS)2α and RET were examined. Two HCC cell lines were subcutaneously implanted on nude mice and mice were treated with 3, 10, 30 mg/kg/day of lenvatinib or vehicle for 14 consecutive days. Tumor volume was measured every 3 days. Mice were sacrificed on day 15 and tumors were processed for histological examination. Blood vessels, microvessel density, necrosis, and apoptosis were also examined. Results: Lenvatinib dose- and time-dependently inhibited growth of all cell lines; however, sensitivity to lenvatinib varied. Apoptosis was not observed in any cell line, and expression of FGFR1, -2, -3 and -4, FGF19, FRS2α, and RET were observed in these cell lines. Cell lines with high expression of these factors showed higher response to lenvatinib. In mice, lenvatinib dose-dependently suppressed tumor growth. Blood vessels and microvessel density were significantly reduced and the rate of necrosis was significantly increased by lenvatinib; apoptosis was not observed. Conclusion: Antiproliferative effects of lenvatinib on liver cancer cells were observed in vitro and in vivo. Lenvatinib may suppress tumor formation by inhibiting angiogenesis, and via an additional direct antiproliferative effect in some liver cancer cells." /> <meta name="og-type" property="og:type" content="article" /> <meta name="og-image" property="og:image" content="https://ar.iiarjournals.org/sites/default/files/highwire/default/covers/acr_default_cover_0.gif" /> <link rel="shortlink" href="/node/56184" /> <link rel="shortcut icon" href="https://ar.iiarjournals.org/sites/default/files/images/favicon.ico" type="image/vnd.microsoft.icon" /> <meta name="viewport" content="width=device-width, initial-scale=1" /> <title>Antiproliferative Effect of Lenvatinib on Human Liver Cancer Cell Lines In Vitro and In Vivo | Anticancer Research</title> <link type="text/css" rel="stylesheet" href="/sites/default/files/advagg_css/css__8dLCIc5LuRVQF8oBfxL3voIXYlUs8gbA_JUyqyaG0y4__TdiQnQPnfzxCsSrrIlg_rwSEd_I4zybroR3qy4yKMs0__hRizlJXedncVv5rdjtoqctDMz6OkI3LghM4uq8DNLG0.css" media="all" /> <style 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class="grid-28 suffix-1 prefix-1 region region-content" id="region-content"> <div class="region-inner region-content-inner"> <a id="main-content"></a> <div class="block block-system block-main block-system-main odd block-without-title" id="block-system-main"> <div class="block-inner clearfix"> <div class="content clearfix"> <div class="panel-display panels-960-layout jcore-2col-layout" > <div class="panel-row-wrapper panel-row-first clearfix"> <div class="top-wrapper"> <div class="panel-panel panel-region-top"> <div class="inside"><div class="panel-pane pane-highwire-article-citation" > <div class="pane-content"> <div class="highwire-article-citation highwire-citation-type-highwire-article node56184--5" data-node-nid="56184" id="top-node-56184--6996246249" data-pisa="anticanres;39/11/5973" data-pisa-master="anticanres;39/11/5973" data-apath="/anticanres/39/11/5973.atom" data-hw-author-tooltip-instance="highwire_author_tooltip"><div class="highwire-cite highwire-cite-highwire-article highwire-citation-jcore-article-title-complete clearfix has-author-tooltip highwire-citation-highwire-article-top-a"> <div class="highwire-cite-overline"><span class="highwire-cite-metadata-article-type highwire-cite-metadata">Research Article</span><span class="separator-pipe"></span><span class="highwire-cite-metadata-art-cat highwire-cite-metadata"><span class="wrapper">Experimental Studies</span></span></div> <div class="highwire-cite-access"><span class="highwire-citation-access highwire-citation-access-check" data-pisa-id="anticanres;39/11/5973" data-atom-uri="/anticanres/39/11/5973.atom" data-request-view="full"></span></div> <h1 class="highwire-cite-title" id="page-title">Antiproliferative Effect of Lenvatinib on Human Liver Cancer Cell Lines <em>In Vitro</em> and <em>In Vivo</em></h1> <div class="highwire-cite-authors"><span class="highwire-citation-authors"><span class="highwire-citation-author first" data-delta="0">SACHIKO OGASAWARA</span>, <span class="highwire-citation-author" data-delta="1">YUTARO MIHARA</span>, <span class="highwire-citation-author" data-delta="2">REIICHIRO KONDO</span>, <span class="highwire-citation-author" data-delta="3">HIRONORI KUSANO</span>, <span class="highwire-citation-author" data-delta="4">JUN AKIBA</span> and <span class="highwire-citation-author" data-delta="5">HIROHISA YANO</span></span></div> <div class="highwire-cite-metadata"><span class="highwire-cite-metadata-journal highwire-cite-metadata">Anticancer Research </span><span class="highwire-cite-metadata-date highwire-cite-metadata">November 2019, </span><span class="highwire-cite-metadata-volume highwire-cite-metadata">39 </span><span class="highwire-cite-metadata-issue highwire-cite-metadata">(11) </span><span class="highwire-cite-metadata-pages highwire-cite-metadata">5973-5982; </span><span class="highwire-cite-metadata-doi highwire-cite-metadata">DOI: https://doi.org/10.21873/anticanres.13802 </span></div> <div class="highwire-cite-extras"><span class="highwire-foxycart-add-to-cart-ahah highwire-foxycart-add-to-cart-ahah" data-text="Add to Cart (%short-price)" data-apath="/anticanres/39/11/5973.atom" data-type="link" data-font-icon="" data-parent-id="56005"></span></div> </div> <div id="hw-article-author-popups-top-node-56184--6996246249" style="display: none;"><div class="author-tooltip-0"><div class="author-tooltip-name">SACHIKO OGASAWARA </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>1</span>Department of Pathology, Kurume University School of Medicine, Kurume, Japan</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=SACHIKO%2BOGASAWARA%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=OGASAWARA%20S&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link"><a href="/search/author1%3ASACHIKO%2BOGASAWARA%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li><li class="author-corresp-email-link last"><span>For correspondence: <a href="mailto:sachiko@med.kurume-u.ac.jp" class="" data-icon-position="" data-hide-link-title="0">sachiko@med.kurume-u.ac.jp</a></span></li></ul></div><div class="author-tooltip-1"><div class="author-tooltip-name">YUTARO MIHARA </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>1</span>Department of Pathology, Kurume University School of Medicine, Kurume, Japan</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=YUTARO%2BMIHARA%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=MIHARA%20Y&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link last"><a href="/search/author1%3AYUTARO%2BMIHARA%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li></ul></div><div class="author-tooltip-2"><div class="author-tooltip-name">REIICHIRO KONDO </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>1</span>Department of Pathology, Kurume University School of Medicine, Kurume, Japan</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=REIICHIRO%2BKONDO%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=KONDO%20R&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link last"><a href="/search/author1%3AREIICHIRO%2BKONDO%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li></ul></div><div class="author-tooltip-3"><div class="author-tooltip-name">HIRONORI KUSANO </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>1</span>Department of Pathology, Kurume University School of Medicine, Kurume, Japan</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=HIRONORI%2BKUSANO%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=KUSANO%20H&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link last"><a href="/search/author1%3AHIRONORI%2BKUSANO%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li></ul></div><div class="author-tooltip-4"><div class="author-tooltip-name">JUN AKIBA </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>2</span>Department of Diagnostic Pathology, Kurume University Hospital, Kurume, Japan</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=JUN%2BAKIBA%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=AKIBA%20J&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link last"><a href="/search/author1%3AJUN%2BAKIBA%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li></ul></div><div class="author-tooltip-5"><div class="author-tooltip-name">HIROHISA YANO </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>1</span>Department of Pathology, Kurume University School of Medicine, Kurume, Japan</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=HIROHISA%2BYANO%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=YANO%20H&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link last"><a href="/search/author1%3AHIROHISA%2BYANO%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li></ul></div></div></div> </div> </div> </div> </div> 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class="panel-pane pane-highwire-panel-tabs-container" > <div class="pane-content"> <div data-panels-ajax-tab-preloaded="jnl_iiar_tab_data" id="panels-ajax-tab-container-highwire_article_tabs" class="panels-ajax-tab-container"><div class="panels-ajax-tab-loading" style ="display:none"><img class="loading" src="https://ar.iiarjournals.org/sites/all/modules/contrib/panels_ajax_tab/images/loading.gif" alt="Loading" title="Loading" /></div><div class="panels-ajax-tab-wrap-jnl_iiar_tab_data"><div class="panel-display panel-1col clearfix" > <div class="panel-panel panel-col"> <div><div class="panel-pane pane-article-fig-data" > <h2 class="pane-title">Article Figures & Data</h2> <div class="pane-content"> <div class="elements-frag-data highwire-markup" id="fig-data"><div id="fig-data-figures" class="group frag-figure"><div class="fig-data-title-jump clearfix"><h3 class="fig-data-group-title">Figures</h3><div class="fig-data-jump-links"></div></div><div class="item-list"><ul class="fig-data-list clearfix" id="fragments-fig"><li class="first"><div class="element-fig-data clearfix figure-caption"><div class="highwire-markup"><div xmlns="http://www.w3.org/1999/xhtml" class="content-block-markup" xmlns:xhtml="http://www.w3.org/1999/xhtml"><div class="fig-expansion " id="F1"><span class="highwire-journal-article-marker-start"></span><div class="highwire-figure"><div class="fig-inline-img-wrapper"><div class="fig-inline-img"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F1.large.jpg?width=800&height=600&carousel=1" title="Antiproliferative effect of lenvatinib. A: Chronological changes in relative viable cell number (% of the control) after adding 30 μM of lenvatinib. B: Relative viable cell number 72 h after adding 1.875, 3.75, 7.5, 15, or 30 μM of lenvatinib. Figures represent the average±SD." class="highwire-fragment fragment-images colorbox-load" rel="gallery-fragment-images-891721672" data-figure-caption="<div class="highwire-markup">Antiproliferative effect of lenvatinib. A: Chronological changes in relative viable cell number (% of the control) after adding 30 μM of lenvatinib. B: Relative viable cell number 72 h after adding 1.875, 3.75, 7.5, 15, or 30 μM of lenvatinib. Figures represent the average±SD.</div>" data-icon-position="" data-hide-link-title="0"><span class="hw-responsive-img"><img class="highwire-fragment fragment-image lazyload" alt="Figure 1." src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" data-src="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F1.medium.gif" width="440" height="245"/><noscript><img class="highwire-fragment fragment-image" alt="Figure 1." src="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F1.medium.gif" width="440" height="245"/></noscript></span></a></div></div><ul class="highwire-figure-links inline"><li class="download-fig first"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F1.large.jpg?download=true" class="highwire-figure-link highwire-figure-link-download" title="Download Figure 1." data-icon-position="" data-hide-link-title="0">Download figure</a></li><li class="new-tab"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F1.large.jpg" class="highwire-figure-link highwire-figure-link-newtab" target="_blank" data-icon-position="" data-hide-link-title="0">Open in new tab</a></li><li class="download-ppt last"><a href="/highwire/powerpoint/58094" class="highwire-figure-link highwire-figure-link-ppt" data-icon-position="" data-hide-link-title="0">Download powerpoint</a></li></ul></div><div class="fig-caption" xmlns:xhtml="http://www.w3.org/1999/xhtml"><span class="fig-label">Figure 1.</span> <p id="p-18">Antiproliferative effect of lenvatinib. A: Chronological changes in relative viable cell number (% of the control) after adding 30 μM of lenvatinib. B: Relative viable cell number 72 h after adding 1.875, 3.75, 7.5, 15, or 30 μM of lenvatinib. Figures represent the average±SD.</p><div class="sb-div caption-clear"></div></div><span class="highwire-journal-article-marker-end"></span></div><span class="related-urls"></span></div></div></div></li><li><div class="element-fig-data clearfix figure-caption"><div class="highwire-markup"><div xmlns="http://www.w3.org/1999/xhtml" class="content-block-markup" xmlns:xhtml="http://www.w3.org/1999/xhtml"><div class="fig-expansion " id="F2"><span class="highwire-journal-article-marker-start"></span><div class="highwire-figure"><div class="fig-inline-img-wrapper"><div class="fig-inline-img"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F2.large.jpg?width=800&height=600&carousel=1" title="Quantitative analysis of lenvatinib-induced apoptosis cells in vitro. Representative data of three cell line experiments are shown." class="highwire-fragment fragment-images colorbox-load" rel="gallery-fragment-images-891721672" data-figure-caption="<div class="highwire-markup">Quantitative analysis of lenvatinib-induced apoptosis cells in vitro. Representative data of three cell line experiments are shown.</div>" data-icon-position="" data-hide-link-title="0"><span class="hw-responsive-img"><img class="highwire-fragment fragment-image lazyload" alt="Figure 2." src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" data-src="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F2.medium.gif" width="440" height="385"/><noscript><img class="highwire-fragment fragment-image" alt="Figure 2." src="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F2.medium.gif" width="440" height="385"/></noscript></span></a></div></div><ul class="highwire-figure-links inline"><li class="download-fig first"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F2.large.jpg?download=true" class="highwire-figure-link highwire-figure-link-download" title="Download Figure 2." data-icon-position="" data-hide-link-title="0">Download figure</a></li><li class="new-tab"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F2.large.jpg" class="highwire-figure-link highwire-figure-link-newtab" target="_blank" data-icon-position="" data-hide-link-title="0">Open in new tab</a></li><li class="download-ppt last"><a href="/highwire/powerpoint/57930" class="highwire-figure-link highwire-figure-link-ppt" data-icon-position="" data-hide-link-title="0">Download powerpoint</a></li></ul></div><div class="fig-caption" xmlns:xhtml="http://www.w3.org/1999/xhtml"><span class="fig-label">Figure 2.</span> <p id="p-24">Quantitative analysis of lenvatinib-induced apoptosis cells in vitro. Representative data of three cell line experiments are shown.</p><div class="sb-div caption-clear"></div></div><span class="highwire-journal-article-marker-end"></span></div><span class="related-urls"></span></div></div></div></li><li><div class="element-fig-data clearfix figure-caption"><div class="highwire-markup"><div xmlns="http://www.w3.org/1999/xhtml" class="content-block-markup" xmlns:xhtml="http://www.w3.org/1999/xhtml"><div class="fig-expansion " id="F3"><span class="highwire-journal-article-marker-start"></span><div class="highwire-figure"><div class="fig-inline-img-wrapper"><div class="fig-inline-img"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F3.large.jpg?width=800&height=600&carousel=1" title="Western blot analysis of fibroblast growth factor receptor 1-4, FGF19, fibroblast growth factor receptor substrate 2α, and RET in different liver cancer cell lines. Lane 1: KIM-1, 2: KYN-1, 3: KYN-2, 4: KYN-3, 5: HAK-1A, 6: HAK-1B, 7: HAK-2, 8: HAK-3, 9: HAK-4, 10: HAK-5, 11: HAK-6, 12: KMCH-1, 13: KMCH-2." class="highwire-fragment fragment-images colorbox-load" rel="gallery-fragment-images-891721672" data-figure-caption="<div class="highwire-markup">Western blot analysis of fibroblast growth factor receptor 1-4, FGF19, fibroblast growth factor receptor substrate 2α, and RET in different liver cancer cell lines. Lane 1: KIM-1, 2: KYN-1, 3: KYN-2, 4: KYN-3, 5: HAK-1A, 6: HAK-1B, 7: HAK-2, 8: HAK-3, 9: HAK-4, 10: HAK-5, 11: HAK-6, 12: KMCH-1, 13: KMCH-2.</div>" data-icon-position="" data-hide-link-title="0"><span class="hw-responsive-img"><img class="highwire-fragment fragment-image lazyload" alt="Figure 3." src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" data-src="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F3.medium.gif" width="440" height="430"/><noscript><img class="highwire-fragment fragment-image" alt="Figure 3." src="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F3.medium.gif" width="440" height="430"/></noscript></span></a></div></div><ul class="highwire-figure-links inline"><li class="download-fig first"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F3.large.jpg?download=true" class="highwire-figure-link highwire-figure-link-download" title="Download Figure 3." data-icon-position="" data-hide-link-title="0">Download figure</a></li><li class="new-tab"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F3.large.jpg" class="highwire-figure-link highwire-figure-link-newtab" target="_blank" data-icon-position="" data-hide-link-title="0">Open in new tab</a></li><li class="download-ppt last"><a href="/highwire/powerpoint/58100" class="highwire-figure-link highwire-figure-link-ppt" data-icon-position="" data-hide-link-title="0">Download powerpoint</a></li></ul></div><div class="fig-caption" xmlns:xhtml="http://www.w3.org/1999/xhtml"><span class="fig-label">Figure 3.</span> <p id="p-26">Western blot analysis of fibroblast growth factor receptor 1-4, FGF19, fibroblast growth factor receptor substrate 2α, and RET in different liver cancer cell lines. Lane 1: KIM-1, 2: KYN-1, 3: KYN-2, 4: KYN-3, 5: HAK-1A, 6: HAK-1B, 7: HAK-2, 8: HAK-3, 9: HAK-4, 10: HAK-5, 11: HAK-6, 12: KMCH-1, 13: KMCH-2.</p><div class="sb-div caption-clear"></div></div><span class="highwire-journal-article-marker-end"></span></div><span class="related-urls"></span></div></div></div></li><li><div class="element-fig-data clearfix figure-caption"><div class="highwire-markup"><div xmlns="http://www.w3.org/1999/xhtml" class="content-block-markup" xmlns:xhtml="http://www.w3.org/1999/xhtml"><div class="fig-expansion " id="F4"><span class="highwire-journal-article-marker-start"></span><div class="highwire-figure"><div class="fig-inline-img-wrapper"><div class="fig-inline-img"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F4.large.jpg?width=800&height=600&carousel=1" title="Antitumor effect of lenvatinib on tumors developed after subcutaneous transplantation of KYN-2 and HAK-1B cells in nude mice. A: Estimated volume of tumors generated by subcutaneously implanted HCC cells over a time course. The mice received 3 (●), 10 (▴), or 30 mg/kg/mouse/day (▪), lenvatinib or vehicle (control) (□). B: All mice were sacrificed on day 15, and tumor weight was measured. Figures represent the average±SD. Significantly different at *p" class="highwire-fragment fragment-images colorbox-load" rel="gallery-fragment-images-891721672" data-figure-caption="<div class="highwire-markup">Antitumor effect of lenvatinib on tumors developed after subcutaneous transplantation of KYN-2 and HAK-1B cells in nude mice. A: Estimated volume of tumors generated by subcutaneously implanted HCC cells over a time course. The mice received 3 (●), 10 (▴), or 30 mg/kg/mouse/day (▪), lenvatinib or vehicle (control) (□). B: All mice were sacrificed on day 15, and tumor weight was measured. Figures represent the average±SD. Significantly different at *p<0.05 or **p<0.01 vs. control.</div>" data-icon-position="" data-hide-link-title="0"><span class="hw-responsive-img"><img class="highwire-fragment fragment-image lazyload" alt="Figure 4." src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" data-src="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F4.medium.gif" width="440" height="332"/><noscript><img class="highwire-fragment fragment-image" alt="Figure 4." src="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F4.medium.gif" width="440" height="332"/></noscript></span></a></div></div><ul class="highwire-figure-links inline"><li class="download-fig first"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F4.large.jpg?download=true" class="highwire-figure-link highwire-figure-link-download" title="Download Figure 4." data-icon-position="" data-hide-link-title="0">Download figure</a></li><li class="new-tab"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F4.large.jpg" class="highwire-figure-link highwire-figure-link-newtab" target="_blank" data-icon-position="" data-hide-link-title="0">Open in new tab</a></li><li class="download-ppt last"><a href="/highwire/powerpoint/58126" class="highwire-figure-link highwire-figure-link-ppt" data-icon-position="" data-hide-link-title="0">Download powerpoint</a></li></ul></div><div class="fig-caption" xmlns:xhtml="http://www.w3.org/1999/xhtml"><span class="fig-label">Figure 4.</span> <p id="p-27">Antitumor effect of lenvatinib on tumors developed after subcutaneous transplantation of KYN-2 and HAK-1B cells in nude mice. A: Estimated volume of tumors generated by subcutaneously implanted HCC cells over a time course. The mice received 3 (●), 10 (▴), or 30 mg/kg/mouse/day (▪), lenvatinib or vehicle (control) (□). B: All mice were sacrificed on day 15, and tumor weight was measured. Figures represent the average±SD. Significantly different at *p<0.05 or **p<0.01 vs. control.</p><div class="sb-div caption-clear"></div></div><span class="highwire-journal-article-marker-end"></span></div><span class="related-urls"></span></div></div></div></li><li><div class="element-fig-data clearfix figure-caption"><div class="highwire-markup"><div xmlns="http://www.w3.org/1999/xhtml" class="content-block-markup" xmlns:xhtml="http://www.w3.org/1999/xhtml"><div class="fig-expansion " id="F5"><span class="highwire-journal-article-marker-start"></span><div class="highwire-figure"><div class="fig-inline-img-wrapper"><div class="fig-inline-img"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F5.large.jpg?width=800&height=600&carousel=1" title="Analysis of lenvatinib-induced apoptosis in human hepatocellular carcinoma tumor HAK-1B subcutaneously transplanted in a nude mouse that received vehicle (A) and in a mouse that received 30 mg/kg of lenvatinib (B). Left panel: Hematoxylin and eosin staining. Right panel: Staining by the TUNEL technique. Scale bar=50 μm." class="highwire-fragment fragment-images colorbox-load" rel="gallery-fragment-images-891721672" data-figure-caption="<div class="highwire-markup">Analysis of lenvatinib-induced apoptosis in human hepatocellular carcinoma tumor HAK-1B subcutaneously transplanted in a nude mouse that received vehicle (A) and in a mouse that received 30 mg/kg of lenvatinib (B). Left panel: Hematoxylin and eosin staining. Right panel: Staining by the TUNEL technique. Scale bar=50 μm.</div>" data-icon-position="" data-hide-link-title="0"><span class="hw-responsive-img"><img class="highwire-fragment fragment-image lazyload" alt="Figure 5." src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" data-src="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F5.medium.gif" width="440" height="320"/><noscript><img class="highwire-fragment fragment-image" alt="Figure 5." src="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F5.medium.gif" width="440" height="320"/></noscript></span></a></div></div><ul class="highwire-figure-links inline"><li class="download-fig first"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F5.large.jpg?download=true" class="highwire-figure-link highwire-figure-link-download" title="Download Figure 5." data-icon-position="" data-hide-link-title="0">Download figure</a></li><li class="new-tab"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F5.large.jpg" class="highwire-figure-link highwire-figure-link-newtab" target="_blank" data-icon-position="" data-hide-link-title="0">Open in new tab</a></li><li class="download-ppt last"><a href="/highwire/powerpoint/58162" class="highwire-figure-link highwire-figure-link-ppt" data-icon-position="" data-hide-link-title="0">Download powerpoint</a></li></ul></div><div class="fig-caption" xmlns:xhtml="http://www.w3.org/1999/xhtml"><span class="fig-label">Figure 5.</span> <p id="p-30">Analysis of lenvatinib-induced apoptosis in human hepatocellular carcinoma tumor HAK-1B subcutaneously transplanted in a nude mouse that received vehicle (A) and in a mouse that received 30 mg/kg of lenvatinib (B). Left panel: Hematoxylin and eosin staining. Right panel: Staining by the TUNEL technique. Scale bar=50 μm.</p><div class="sb-div caption-clear"></div></div><span class="highwire-journal-article-marker-end"></span></div><span class="related-urls"></span></div></div></div></li><li><div class="element-fig-data clearfix figure-caption"><div class="highwire-markup"><div xmlns="http://www.w3.org/1999/xhtml" class="content-block-markup" xmlns:xhtml="http://www.w3.org/1999/xhtml"><div class="fig-expansion " id="F6"><span class="highwire-journal-article-marker-start"></span><div class="highwire-figure"><div class="fig-inline-img-wrapper"><div class="fig-inline-img"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F6.large.jpg?width=800&height=600&carousel=1" title="Effect of lenvatinib on suppression of angiogenesis in tumors developed after subcutaneous transplantation of hepatocellular carcinoma cells. Immunohistochemical staining of CD34 in KYN-2 cell tumors (A-D) and HAK-1B cell tumors (E-H). Scale bar=50 μm. Mice received vehicle (control) (A, E), or lenvatinib of at 3 (B, F), 10 (C, G), or (D, H) 30 mg/kg/mouse/day." class="highwire-fragment fragment-images colorbox-load" rel="gallery-fragment-images-891721672" data-figure-caption="<div class="highwire-markup">Effect of lenvatinib on suppression of angiogenesis in tumors developed after subcutaneous transplantation of hepatocellular carcinoma cells. Immunohistochemical staining of CD34 in KYN-2 cell tumors (A-D) and HAK-1B cell tumors (E-H). Scale bar=50 μm. Mice received vehicle (control) (A, E), or lenvatinib of at 3 (B, F), 10 (C, G), or (D, H) 30 mg/kg/mouse/day.</div>" data-icon-position="" data-hide-link-title="0"><span class="hw-responsive-img"><img class="highwire-fragment fragment-image lazyload" alt="Figure 6." src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" data-src="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F6.medium.gif" width="292" height="440"/><noscript><img class="highwire-fragment fragment-image" alt="Figure 6." src="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F6.medium.gif" width="292" height="440"/></noscript></span></a></div></div><ul class="highwire-figure-links inline"><li class="download-fig first"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F6.large.jpg?download=true" class="highwire-figure-link highwire-figure-link-download" title="Download Figure 6." data-icon-position="" data-hide-link-title="0">Download figure</a></li><li class="new-tab"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F6.large.jpg" class="highwire-figure-link highwire-figure-link-newtab" target="_blank" data-icon-position="" data-hide-link-title="0">Open in new tab</a></li><li class="download-ppt last"><a href="/highwire/powerpoint/57989" class="highwire-figure-link highwire-figure-link-ppt" data-icon-position="" data-hide-link-title="0">Download powerpoint</a></li></ul></div><div class="fig-caption" xmlns:xhtml="http://www.w3.org/1999/xhtml"><span class="fig-label">Figure 6.</span> <p id="p-34">Effect of lenvatinib on suppression of angiogenesis in tumors developed after subcutaneous transplantation of hepatocellular carcinoma cells. Immunohistochemical staining of CD34 in KYN-2 cell tumors (A-D) and HAK-1B cell tumors (E-H). Scale bar=50 μm. Mice received vehicle (control) (A, E), or lenvatinib of at 3 (B, F), 10 (C, G), or (D, H) 30 mg/kg/mouse/day.</p><div class="sb-div caption-clear"></div></div><span class="highwire-journal-article-marker-end"></span></div><span class="related-urls"></span></div></div></div></li><li class="last"><div class="element-fig-data clearfix figure-caption"><div class="highwire-markup"><div xmlns="http://www.w3.org/1999/xhtml" class="content-block-markup" xmlns:xhtml="http://www.w3.org/1999/xhtml"><div class="fig-expansion " id="F7"><span class="highwire-journal-article-marker-start"></span><div class="highwire-figure"><div class="fig-inline-img-wrapper"><div class="fig-inline-img"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F7.large.jpg?width=800&height=600&carousel=1" title="Effect of lenvatinib on blood vessel frequency (A), microvessel density (B), and necrosis rate of tumors (C) in nude mice. Figures represent the average±SD. Significantly different at *p" class="highwire-fragment fragment-images colorbox-load" rel="gallery-fragment-images-891721672" data-figure-caption="<div class="highwire-markup">Effect of lenvatinib on blood vessel frequency (A), microvessel density (B), and necrosis rate of tumors (C) in nude mice. Figures represent the average±SD. Significantly different at *p<0.05, **p<0.01, or ***p<0.001 vs. control.</div>" data-icon-position="" data-hide-link-title="0"><span class="hw-responsive-img"><img class="highwire-fragment fragment-image lazyload" alt="Figure 7." src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" data-src="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F7.medium.gif" width="440" height="260"/><noscript><img class="highwire-fragment fragment-image" alt="Figure 7." src="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F7.medium.gif" width="440" height="260"/></noscript></span></a></div></div><ul class="highwire-figure-links inline"><li class="download-fig first"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F7.large.jpg?download=true" class="highwire-figure-link highwire-figure-link-download" title="Download Figure 7." data-icon-position="" data-hide-link-title="0">Download figure</a></li><li class="new-tab"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F7.large.jpg" class="highwire-figure-link highwire-figure-link-newtab" target="_blank" data-icon-position="" data-hide-link-title="0">Open in new tab</a></li><li class="download-ppt last"><a href="/highwire/powerpoint/58028" class="highwire-figure-link highwire-figure-link-ppt" data-icon-position="" data-hide-link-title="0">Download powerpoint</a></li></ul></div><div class="fig-caption" xmlns:xhtml="http://www.w3.org/1999/xhtml"><span class="fig-label">Figure 7.</span> <p id="p-35">Effect of lenvatinib on blood vessel frequency (A), microvessel density (B), and necrosis rate of tumors (C) in nude mice. Figures represent the average±SD. Significantly different at *p<0.05, **p<0.01, or ***p<0.001 vs. control.</p><div class="sb-div caption-clear"></div></div><span class="highwire-journal-article-marker-end"></span></div><span class="related-urls"></span></div></div></div></li></ul></div></div></div> </div> </div> </div> </div> </div> </div></div> </div> </div> <div class="panel-separator"></div><div class="panel-pane pane-highwire-node-pager" > <div class="pane-content"> <div class="pager highwire-pager pager-mini clearfix highwire-node-pager highwire-article-pager"><span class="pager-prev"><a href="/content/39/11/5963" title="Identification of Matrix Metalloproteinase 11 as a Prognostic Biomarker in Pancreatic Cancer" rel="prev" class="pager-link-prev link-icon"><span class="icon-circle-arrow-left"></span> <span class="title">Previous</span></a></span><span class="pager-next"><a href="/content/39/11/5983" title="DJ-1 Contributes to Self-renewal of Stem Cells in the U87-MG Glioblastoma Cell Line" rel="next" 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