Targeting hexokinase 2 to enhance anticancer efficacy of trichosanthin in HeLa and SCC25 cell models

<!DOCTYPE html> <html lang="en-US" xml:lang="en-US"> <head> <meta charset="utf-8"> <meta name="viewport" content="width=device-width, initial-scale=1.0"> <title> Targeting hexokinase 2 to enhance anticancer efficacy of trichosanthin in HeLa and SCC25 cell models | ADMET and DMPK </title> <link rel="icon" href="https://pub.iapchem.org/ojs/public/journals/4/favicon_en_US.jpg"> <meta name="generator" content="Open Journal Systems 3.3.0.13"> <link rel="schema.DC" href="http://purl.org/dc/elements/1.1/" /> <meta name="DC.Creator.PersonalName" content="Yan Zhou"/> <meta name="DC.Creator.PersonalName" content="Maoxin Ran"/> <meta name="DC.Creator.PersonalName" content="Wenying Shan"/> <meta name="DC.Creator.PersonalName" content="Kaifang Wang"/> <meta name="DC.Creator.PersonalName" content="Ou Sha"/> <meta name="DC.Creator.PersonalName" content="Kin Tam"/> <meta name="DC.Date.created" scheme="ISO8601" content="2024-09-12"/> <meta name="DC.Date.dateSubmitted" scheme="ISO8601" content="2024-08-07"/> <meta name="DC.Date.issued" scheme="ISO8601" content="2024-07-24"/> <meta name="DC.Date.modified" scheme="ISO8601" content="2024-09-22"/> <meta name="DC.Description" xml:lang="en" content="Background and purpose: Trichosanthin (TCS) is a plant-based ribosome-inactivating protein exhibiting a range of pharmacological properties, including abortifacient and anticancer. However, the routine clinical use in cancer treatment was hampered by its antigenicity. Hexokinase 2 (HK2) is a pivotal regulator of glycolysis, where aberrant expression is observed in many cancers. This study investigates the anticancer effects and mechanisms of TCS in combination with benserazide (Benz), a HK2 inhibitor, in Hela and SCC25 cancer models. Experimental approach: MTT, colony-formation and cell cycle assays were performed to assess the cytotoxic effects of TCS and Benz in HeLa and SCC25 cells. Seahorse assay, western blotting, flow cytometry analysis and RNA sequencing were employed to investigate the pharmacological effects of the combo treatment. SCC25 cell xenograft mouse model was established for in vivo efficacy study. Key results: Combined use of TCS and Benz exhibited synergistic anticancer effects in both Hela and SCC25 cell models. The observed synergistic effects were attributed to the modulation of glycolysis by targeting HK2, leading to reduced lactate production and increased ROS accumulation which further inhibited colony formation and cell cycle progression, as well as triggered apoptosis. Moreover, this combination effectively inhibited NFκB/ERK signalling pathways, which were found to be significantly activated upon single use of TCS. It was found that the combination significantly suppressed the tumour growth in SCC25 cell xenograft mouse model. Conclusion: Our findings suggested that targeting HK2 and modulating glycolysis may offer a promising avenue for improving the therapeutic outcomes of TCS-based anticancer treatments. "/> <meta name="DC.Format" scheme="IMT" content="application/pdf"/> <meta name="DC.Identifier" content="2455"/> <meta name="DC.Identifier.DOI" content="10.5599/admet.2455"/> <meta name="DC.Identifier.URI" content="https://pub.iapchem.org/ojs/index.php/admet/article/view/2455"/> <meta name="DC.Language" scheme="ISO639-1" content="en"/> <meta name="DC.Rights" content="Copyright (c) 2024 ADMET and DMPK"/> <meta name="DC.Rights" content=""/> <meta name="DC.Source" content="ADMET and DMPK"/> <meta name="DC.Source.ISSN" content="1848-7718"/> <meta name="DC.Source.URI" content="https://pub.iapchem.org/ojs/index.php/admet"/> <meta name="DC.Subject" xml:lang="en" content="Ribosome-inactivating protein"/> <meta name="DC.Subject" xml:lang="en" content="Glycolysis"/> <meta name="DC.Subject" xml:lang="en" content="Drug combination"/> <meta name="DC.Subject" xml:lang="en" content="Synergistic effect"/> <meta name="DC.Subject" xml:lang="en" content="Cancer therapy"/> <meta name="DC.Title" content="Targeting hexokinase 2 to enhance anticancer efficacy of trichosanthin in HeLa and SCC25 cell models"/> <meta name="DC.Type" content="Text.Serial.Journal"/> <meta name="DC.Type.articleType" content="Original Scientific Articles"/> <meta name="gs_meta_revision" content="1.1"/> <meta name="citation_journal_title" content="ADMET and DMPK"/> <meta name="citation_journal_abbrev" content="ADMET DMPK"/> <meta name="citation_issn" content="1848-7718"/> <meta name="citation_author" content="Yan Zhou"/> <meta name="citation_author_institution" content="Faculty of Health Sciences, University of Macau, Taipa, Macau"/> <meta name="citation_author" content="Maoxin Ran"/> <meta name="citation_author_institution" content="School of Dentistry, Shenzhen University Medical School, Shenzhen, China"/> <meta name="citation_author" content="Wenying Shan"/> <meta name="citation_author_institution" content="Faculty of Health Sciences, University of Macau, Taipa, Macau"/> <meta name="citation_author" content="Kaifang Wang"/> <meta name="citation_author_institution" content="Faculty of Health Sciences, University of Macau, Taipa, Macau and School of Dentistry, Shenzhen University Medical School, Shenzhen, China"/> <meta name="citation_author" content="Ou Sha"/> <meta name="citation_author_institution" content="School of Dentistry, Shenzhen University Medical School, Shenzhen, China"/> <meta name="citation_author" content="Kin Tam"/> <meta name="citation_author_institution" content="Faculty of Health Sciences, University of Macau, Taipa, Macau"/> <meta name="citation_title" content="Targeting hexokinase 2 to enhance anticancer efficacy of trichosanthin in HeLa and SCC25 cell models"/> <meta name="citation_language" content="en"/> <meta name="citation_date" content="2024/09/12"/> <meta name="citation_doi" content="10.5599/admet.2455"/> <meta name="citation_abstract_html_url" content="https://pub.iapchem.org/ojs/index.php/admet/article/view/2455"/> <meta name="citation_keywords" xml:lang="en" content="Ribosome-inactivating protein"/> <meta name="citation_keywords" xml:lang="en" content="Glycolysis"/> <meta name="citation_keywords" xml:lang="en" content="Drug combination"/> <meta name="citation_keywords" xml:lang="en" content="Synergistic effect"/> <meta name="citation_keywords" xml:lang="en" content="Cancer therapy"/> <meta name="citation_pdf_url" content="https://pub.iapchem.org/ojs/index.php/admet/article/download/2455/2207"/> <meta name="citation_reference" content="J. 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class="separator">/</span> </li> <li class="current" aria-current="page"> <span aria-current="page"> Original Scientific Articles </span> </li> </ol> </nav> <article class="obj_article_details"> <h1 class="page_title"> Targeting hexokinase 2 to enhance anticancer efficacy of trichosanthin in HeLa and SCC25 cell models </h1> <div class="row"> <div class="main_entry"> <section class="item authors"> <h2 class="pkp_screen_reader">Authors</h2> <ul class="authors"> <li> <span class="name"> Yan Zhou </span> <span class="affiliation"> Faculty of Health Sciences, University of Macau, Taipa, Macau </span> <span class="orcid"> <svg class="orcid_icon" viewBox="0 0 256 256" aria-hidden="true"> <style type="text/css"> .st0{fill:#A6CE39;} .st1{fill:#FFFFFF;} </style> <path class="st0" d="M256,128c0,70.7-57.3,128-128,128C57.3,256,0,198.7,0,128C0,57.3,57.3,0,128,0C198.7,0,256,57.3,256,128z"/> <g> <path class="st1" d="M86.3,186.2H70.9V79.1h15.4v48.4V186.2z"/> <path class="st1" d="M108.9,79.1h41.6c39.6,0,57,28.3,57,53.6c0,27.5-21.5,53.6-56.8,53.6h-41.8V79.1z M124.3,172.4h24.5 c34.9,0,42.9-26.5,42.9-39.7c0-21.5-13.7-39.7-43.7-39.7h-23.7V172.4z"/> <path class="st1" d="M88.7,56.8c0,5.5-4.5,10.1-10.1,10.1c-5.6,0-10.1-4.6-10.1-10.1c0-5.6,4.5-10.1,10.1-10.1 C84.2,46.7,88.7,51.3,88.7,56.8z"/> </g> </svg> <a href="https://orcid.org/0000-0003-4858-6648" target="_blank"> https://orcid.org/0000-0003-4858-6648 </a> </span> </li> <li> <span class="name"> Maoxin Ran </span> <span class="affiliation"> School of Dentistry, Shenzhen University Medical School, Shenzhen, China </span> <span class="orcid"> <svg class="orcid_icon" viewBox="0 0 256 256" aria-hidden="true"> <style type="text/css"> .st0{fill:#A6CE39;} .st1{fill:#FFFFFF;} </style> <path class="st0" d="M256,128c0,70.7-57.3,128-128,128C57.3,256,0,198.7,0,128C0,57.3,57.3,0,128,0C198.7,0,256,57.3,256,128z"/> <g> <path class="st1" d="M86.3,186.2H70.9V79.1h15.4v48.4V186.2z"/> <path class="st1" d="M108.9,79.1h41.6c39.6,0,57,28.3,57,53.6c0,27.5-21.5,53.6-56.8,53.6h-41.8V79.1z M124.3,172.4h24.5 c34.9,0,42.9-26.5,42.9-39.7c0-21.5-13.7-39.7-43.7-39.7h-23.7V172.4z"/> <path class="st1" d="M88.7,56.8c0,5.5-4.5,10.1-10.1,10.1c-5.6,0-10.1-4.6-10.1-10.1c0-5.6,4.5-10.1,10.1-10.1 C84.2,46.7,88.7,51.3,88.7,56.8z"/> </g> </svg> <a href="https://orcid.org/0009-0000-1053-6122" target="_blank"> https://orcid.org/0009-0000-1053-6122 </a> </span> </li> <li> <span class="name"> Wenying Shan </span> <span class="affiliation"> Faculty of Health Sciences, University of Macau, Taipa, Macau </span> <span class="orcid"> <svg class="orcid_icon" viewBox="0 0 256 256" aria-hidden="true"> <style type="text/css"> .st0{fill:#A6CE39;} .st1{fill:#FFFFFF;} </style> <path class="st0" d="M256,128c0,70.7-57.3,128-128,128C57.3,256,0,198.7,0,128C0,57.3,57.3,0,128,0C198.7,0,256,57.3,256,128z"/> <g> <path class="st1" d="M86.3,186.2H70.9V79.1h15.4v48.4V186.2z"/> <path class="st1" d="M108.9,79.1h41.6c39.6,0,57,28.3,57,53.6c0,27.5-21.5,53.6-56.8,53.6h-41.8V79.1z M124.3,172.4h24.5 c34.9,0,42.9-26.5,42.9-39.7c0-21.5-13.7-39.7-43.7-39.7h-23.7V172.4z"/> <path class="st1" d="M88.7,56.8c0,5.5-4.5,10.1-10.1,10.1c-5.6,0-10.1-4.6-10.1-10.1c0-5.6,4.5-10.1,10.1-10.1 C84.2,46.7,88.7,51.3,88.7,56.8z"/> </g> </svg> <a href="https://orcid.org/0000-0002-3922-1674" target="_blank"> https://orcid.org/0000-0002-3922-1674 </a> </span> </li> <li> <span class="name"> Kaifang Wang </span> <span class="affiliation"> Faculty of Health Sciences, University of Macau, Taipa, Macau and School of Dentistry, Shenzhen University Medical School, Shenzhen, China </span> <span class="orcid"> <svg class="orcid_icon" viewBox="0 0 256 256" aria-hidden="true"> <style type="text/css"> .st0{fill:#A6CE39;} .st1{fill:#FFFFFF;} </style> <path class="st0" d="M256,128c0,70.7-57.3,128-128,128C57.3,256,0,198.7,0,128C0,57.3,57.3,0,128,0C198.7,0,256,57.3,256,128z"/> <g> <path class="st1" d="M86.3,186.2H70.9V79.1h15.4v48.4V186.2z"/> <path class="st1" d="M108.9,79.1h41.6c39.6,0,57,28.3,57,53.6c0,27.5-21.5,53.6-56.8,53.6h-41.8V79.1z M124.3,172.4h24.5 c34.9,0,42.9-26.5,42.9-39.7c0-21.5-13.7-39.7-43.7-39.7h-23.7V172.4z"/> <path class="st1" d="M88.7,56.8c0,5.5-4.5,10.1-10.1,10.1c-5.6,0-10.1-4.6-10.1-10.1c0-5.6,4.5-10.1,10.1-10.1 C84.2,46.7,88.7,51.3,88.7,56.8z"/> </g> </svg> <a href="https://orcid.org/0000-0003-0599-473X" target="_blank"> https://orcid.org/0000-0003-0599-473X </a> </span> </li> <li> <span class="name"> Ou Sha </span> <span class="affiliation"> School of Dentistry, Shenzhen University Medical School, Shenzhen, China </span> <span class="orcid"> <svg class="orcid_icon" viewBox="0 0 256 256" aria-hidden="true"> <style type="text/css"> .st0{fill:#A6CE39;} .st1{fill:#FFFFFF;} </style> <path class="st0" d="M256,128c0,70.7-57.3,128-128,128C57.3,256,0,198.7,0,128C0,57.3,57.3,0,128,0C198.7,0,256,57.3,256,128z"/> <g> <path class="st1" d="M86.3,186.2H70.9V79.1h15.4v48.4V186.2z"/> <path class="st1" d="M108.9,79.1h41.6c39.6,0,57,28.3,57,53.6c0,27.5-21.5,53.6-56.8,53.6h-41.8V79.1z M124.3,172.4h24.5 c34.9,0,42.9-26.5,42.9-39.7c0-21.5-13.7-39.7-43.7-39.7h-23.7V172.4z"/> <path class="st1" d="M88.7,56.8c0,5.5-4.5,10.1-10.1,10.1c-5.6,0-10.1-4.6-10.1-10.1c0-5.6,4.5-10.1,10.1-10.1 C84.2,46.7,88.7,51.3,88.7,56.8z"/> </g> </svg> <a href="https://orcid.org/0000-0003-1254-1683" target="_blank"> https://orcid.org/0000-0003-1254-1683 </a> </span> </li> <li> <span class="name"> Kin Tam </span> <span class="affiliation"> Faculty of Health Sciences, University of Macau, Taipa, Macau </span> <span class="orcid"> <svg class="orcid_icon" viewBox="0 0 256 256" aria-hidden="true"> <style type="text/css"> .st0{fill:#A6CE39;} .st1{fill:#FFFFFF;} </style> <path class="st0" d="M256,128c0,70.7-57.3,128-128,128C57.3,256,0,198.7,0,128C0,57.3,57.3,0,128,0C198.7,0,256,57.3,256,128z"/> <g> <path class="st1" d="M86.3,186.2H70.9V79.1h15.4v48.4V186.2z"/> <path class="st1" d="M108.9,79.1h41.6c39.6,0,57,28.3,57,53.6c0,27.5-21.5,53.6-56.8,53.6h-41.8V79.1z M124.3,172.4h24.5 c34.9,0,42.9-26.5,42.9-39.7c0-21.5-13.7-39.7-43.7-39.7h-23.7V172.4z"/> <path class="st1" d="M88.7,56.8c0,5.5-4.5,10.1-10.1,10.1c-5.6,0-10.1-4.6-10.1-10.1c0-5.6,4.5-10.1,10.1-10.1 C84.2,46.7,88.7,51.3,88.7,56.8z"/> </g> </svg> <a href="https://orcid.org/0000-0001-5507-8524" target="_blank"> https://orcid.org/0000-0001-5507-8524 </a> </span> </li> </ul> </section> <section class="item doi"> <h2 class="label"> DOI: </h2> <span class="value"> <a href="https://doi.org/10.5599/admet.2455"> https://doi.org/10.5599/admet.2455 </a> </span> </section> <section class="item keywords"> <h2 class="label"> Keywords: </h2> <span class="value"> Ribosome-inactivating protein, Glycolysis, Drug combination, Synergistic effect, Cancer therapy </span> </section> <div class="item cover_image"> <div class="sub_item"> <img src="https://pub.iapchem.org/ojs/public/journals/4/submission_2455_2163_coverImage_en_US.jpg" alt="Graphical Abstract" > </div> </div> <section class="item abstract"> <h2 class="label">Abstract</h2> <p><strong>Background and purpose:</strong> Trichosanthin (TCS) is a plant-based ribosome-inactivating protein exhibiting a range of pharmacological properties, including abortifacient and anticancer. However, the routine clinical use in cancer treatment was hampered by its antigenicity. Hexokinase 2 (HK2) is a pivotal regulator of glycolysis, where aberrant expression is observed in many cancers. This study investigates the anticancer effects and mechanisms of TCS in combination with benserazide (Benz), a HK2 inhibitor, in Hela and SCC25 cancer models. <strong>Experimental approach:</strong> MTT, colony-formation and cell cycle assays were performed to assess the cytotoxic effects of TCS and Benz in HeLa and SCC25 cells. Seahorse assay, western blotting, flow cytometry analysis and RNA sequencing were employed to investigate the pharmacological effects of the combo treatment. SCC25 cell xenograft mouse model was established for in vivo efficacy study. <strong>Key results:</strong> Combined use of TCS and Benz exhibited synergistic anticancer effects in both Hela and SCC25 cell models. The observed synergistic effects were attributed to the modulation of glycolysis by targeting HK2, leading to reduced lactate production and increased ROS accumulation which further inhibited colony formation and cell cycle progression, as well as triggered apoptosis. Moreover, this combination effectively inhibited NFκB/ERK signalling pathways, which were found to be significantly activated upon single use of TCS. It was found that the combination significantly suppressed the tumour growth in SCC25 cell xenograft mouse model. <strong>Conclusion:</strong> Our findings suggested that targeting HK2 and modulating glycolysis may offer a promising avenue for improving the therapeutic outcomes of TCS-based anticancer treatments.</p> <p> </p> </section> <div class="item downloads_chart"> <h3 class="label"> Downloads </h3> <div class="value"> <canvas class="usageStatsGraph" data-object-type="Submission" data-object-id="2455"></canvas> <div class="usageStatsUnavailable" data-object-type="Submission" data-object-id="2455"> Download data is not yet available. </div> </div> </div> <section class="item references"> <h2 class="label"> References </h2> <div class="value"> <p>J. Luo, N.L. Solimini, S.J. Elledge. Principles of cancer therapy: oncogene and non-oncogene addiction. 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<li> <a href="https://search.crossref.org/funding?q=501100006469">Fundo para o Desenvolvimento das Ciências e da Tecnologia</a> <br /> Grant numbers 0138/2022/A </li> <li> <a href="https://search.crossref.org/funding?q=501100019492">National Natural Science Foundation of China-China Academy of General Technology Joint Fund for Basic Research</a> <br /> Grant numbers 81773939 </li> <li> <a href="https://search.crossref.org/funding?q=100017380">Science and Technology Foundation of Shenzhen City</a> <br /> Grant numbers JCYJ20210324094005015 </li> </ul> </div> </div> </div> </div> </article> <div id="articlesBySameAuthorList"> <h3>Most read articles by the same author(s)</h3> <ul> <li> Kin Tam, <a href="https://pub.iapchem.org/ojs/index.php/admet/article/view/7"> The Roles of Doxorubicin in Hepatocellular Carcinoma </a>, <a href="https://pub.iapchem.org/ojs/index.php/admet/issue/view/3"> ADMET and DMPK: Vol. 1 No. 3 (2013) </a> </li> <li> Kin Tam, <a 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Targeting hexokinase 2 to enhance anticancer efficacy of trichosanthin in HeLa and SCC25 cell models | ADMET and DMPK