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Existing therapies for advanced disease include atezolizumab and bevacizumab, as well as sorafenib, but most patients develop resistance to sorafenib, limiting long-term benefit. This review compiles molecular evidence on how sorafenib alone, or combined with valproic acid and metformin, induces cell death, emphasizing intracellular signaling and cancer hallmark mechanisms.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/mechanistic-insights-about-sorafenib-valproic-acid-and-metformin-induced-cell-death-in-hepatocellular-carcinoma-review/331844/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/mechanistic-insights-about-sorafenib-valproic-acid-and-metformin-induced-cell-death-in-hepatocellular-carcinoma-review/331844.png","ImageObject",300,407,{"name":92,"@type":93},"Himbo","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-31","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":29},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What cancer type and key problem does the review focus on?","Question",{"text":112,"@type":113},"The review focuses on hepatocellular carcinoma (HCC) and the main challenge of treatment resistance to sorafenib in most patients.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"Which drugs are discussed for inducing cell death?",{"text":117,"@type":113},"The review analyzes cell-death mechanisms driven by sorafenib administered alone and in combination with valproic acid and metformin.",{"name":119,"@type":110,"acceptedAnswer":120},"What treatment options for advanced HCC are mentioned?",{"text":121,"@type":113},"Advanced HCC treatments mentioned include atezolizumab and bevacizumab as immunological options, alongside sorafenib as a therapy where resistance often develops.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},331844,1790220804,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":29,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145,"preview_page_count":4},687197100911,"https://ap-avatar.wpscdn.com/avatar/a000239b6f1da00475?x-image-process=image/resize,m_fixed,w_180,h_180&k=1785132997149421697","Review  \nMechanistic Insights about Sorafenib-, Valproic Acid-and Metformin-Induced Cell Death in Hepatocellular Carcinoma  \nEdgar Xchel Franco-Juárez 1,2, Vianey González-Villasana 2, María Elena Camacho-Moll 1, Luisa Rendón-Garlant 2, Patricia Nefertari Ramírez-Flores 1,3, Beatriz Silva-Ramírez 4, Katia Peñuelas-Urquides 1,  \nEthel Daniela Cabello-Ruiz 2, Fabiola Castorena-Torres 3 and Mario Bermúdez de León 1, *  \nCitation: Franco-Juárez, E.X.;  \nGonzález-Villasana, V.;  \nCamacho-Moll, M.E.; Rendón-Garlant, L.; Ramírez-Flores, P.N.;  \nSilva-Ramírez, B.; Peñuelas-Urquides, K.; Cabello-Ruiz, E.D.;  \nCastorena-Torres, F.; Bermúdez de León, M. Mechanistic Insights about Sorafenib-, Valproic Acid-and Metformin-Induced Cell Death in Hepatocellular Carcinoma.  \nInt. J. Mol. Sci. 2024, 25, 1760. [https://](https://)[ ](https://)[doi.org/10.3390/ijms25031760](doi.org/10.3390/ijms25031760)  \nAcademic Editors: Georg C. Huttererand Nam Deuk Kim  \nReceived: 9 October 2023  \nRevised: 12 December 2023  \nAccepted: 13 December 2023  \nPublished: 1 February 2024  \nCopyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 Departamento de Biología Molecular, Centro de Investigación Biomédica del Noreste, Instituto Mexicano del Seguro Social, Monterrey 64720, Nuevo Leon, Mexico; [xchelfj@yahoo.com](xchelfj@yahoo.com) (E.X.F.-J.);  \n[maria.camachomo@imss.gob.mx](maria.camachomo@imss.gob.mx) (M.E.C.-M.); [a00835273@tec.mx](a00835273@tec.mx) (P.N.R.-F.);  \n[katia.penuelasu@imss.gob.mx](katia.penuelasu@imss.gob.mx) (K.P.-U.)  \n2 Facultad de Ciencias Biológicas, Universidad Autónoma de Nuevo León, San Nicolás de los Garza 66451, Nuevo Leon, Mexico; [vianey.gonzalezvl@uanl.edu.mx](vianey.gonzalezvl@uanl.edu.mx) (V.G.-V.); [luisa.rendon29@gmail.com](luisa.rendon29@gmail.com) (L.R.-G.); [ethel.cabellorz@uanl.edu.mx](ethel.cabellorz@uanl.edu.mx) (E.D.C.-R.)  \n3 Tecnológico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey 64710, Nuevo Leon, Mexico; [fcastorena@tec.mx](fcastorena@tec.mx)  \n4 Departamento de Inmunogenética, Centro de Investigación Biomédica del Noreste, Instituto Mexicano del Seguro Social, Monterrey 64720, Nuevo Leon, Mexico; [silbear2002@yahoo.es](silbear2002@yahoo.es)  \n* [Correspondence: mario.bermudez@imss.gob.mx](Correspondence: mario.bermudez@imss.gob.mx); Tel.: +52-(81)8190-4036  \nAbstract: Hepatocellular carcinoma (HCC) is among the main causes of death by cancer worldwide, representing about 80–90% of all liver cancers. Treatments available for advanced HCC include atezolizumab, bevacizumab, sorafenib, among others. Atezolizumab and bevacizumab are immunological options recently incorporated into first-line treatments, along with sorafenib, for which great treatment achievements have been reached. However, sorafenib resistance is developed in most patients, and therapeutical combinations targeting cancer hallmark mechanisms and intracellular signaling have been proposed. In this review, we compiled evidence of the mechanisms of cell death caused by sorafenib administered alone or in combination with valproic acid and metformin and discussed them from a molecular perspective.  \nKeywords: hepatocellular carcinoma; sorafenib; apoptosis; autophagy; metformin; valproic acid; cell death; drug repurposing  \n1. Introduction  \nThe most recent report provided by GLOBOCAN in 2020 positions hepatocellular carcinoma (HCC) in the sixth place with respect to worldwide cancer incidence, with 905,677 new cases, and in the third place with respect to cancer-related mortality, with 830,180 deaths [1] . From 2008 to 2020, the rate of new HCC cases increased by ~20%, from 748,000 to 905,677, and HCC-related mortality showed the same t","cbCaifsnR1zPUpFW","https://ap.wps.com/l/cbCaifsnR1zPUpFW","pdf",2067749,18,"English","# Abstract\n# Keywords\n# 1. Introduction\n# 2. Risk Factors and Disease Context","[{\"question\":\"What cancer type and key problem does the review focus on?\",\"answer\":\"The review focuses on hepatocellular carcinoma (HCC) and the main challenge of treatment resistance to sorafenib in most patients.\"},{\"question\":\"Which drugs are discussed for inducing cell death?\",\"answer\":\"The review analyzes cell-death mechanisms driven by sorafenib administered alone and in combination with valproic acid and metformin.\"},{\"question\":\"What treatment options for advanced HCC are mentioned?\",\"answer\":\"Advanced HCC treatments mentioned include atezolizumab and bevacizumab as immunological options, alongside sorafenib as a therapy where resistance often develops.\"}]","Mechanistic Insights about Sorafenib-, Valproic Acid-and Metformin-Induced Cell Death in Hepatocellular Carcinoma - Review | PDF",1789995444,45]