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SFN concentration-dependently reduced total HDAC activity and increased histone H3 acetylation while synergizing with GEM to suppress viability and proliferation via G2/M cell-cycle arrest and caspase-3–associated apoptosis. SFN also inhibited invasion and decreased pro-angiogenic and EMT-related markers, while combination treatment further attenuated tumor growth, Ki67+ proliferation, and TUNEL+ apoptosis responses, alongside modulation of p21/p-Chk2 and VEGF/EMT signaling in vivo.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/healthcare/","Healthcare",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/sulforaphane-potentiates-gemcitabine-mediated-anti-cancer-effects-against-intrahepatic-cholangiocarcinoma-inhibiting-hdac-activity/382147/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/sulforaphane-potentiates-gemcitabine-mediated-anti-cancer-effects-against-intrahepatic-cholangiocarcinoma-inhibiting-hdac-activity/382147.png","ImageObject",300,407,{"name":42,"@type":43},"Jiven","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-10-28","2026-09-24",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",13,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"Why is iCCA prognosis poor and what drives chemotherapy resistance?","Question",{"text":63,"@type":64},"iCCA has poor prognosis due to early local invasion, metastasis, and insufficient early diagnosis. 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It also prevents GEM-mediated induction of epithelial–mesenchymal transition (EMT) and reduces tumor neovascularization markers in vivo.","https://schema.org",{"og:url":32,"og:type":75,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":77,"canonical":32},"index,follow",{"doc_id":79,"site_id":7},382147,1790293321,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,106,110,115,120,123,127],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Story & Novel",90,"story-novel",{"id":26,"doc_module":4,"doc_module_name":25,"category_name":89,"show_sort_weight":90,"slug":91},"Literature",80,"literature",{"id":33,"doc_module":4,"doc_module_name":25,"category_name":93,"show_sort_weight":94,"slug":95},"Exam",70,"exam",{"id":97,"doc_module":4,"doc_module_name":25,"category_name":98,"show_sort_weight":99,"slug":100},5,"Comic",60,"comic",{"id":102,"doc_module":4,"doc_module_name":25,"category_name":103,"show_sort_weight":104,"slug":105},6,"Technology",50,"technology",{"id":107,"doc_module":4,"doc_module_name":25,"category_name":29,"show_sort_weight":108,"slug":109},7,40,"healthcare",{"id":111,"doc_module":4,"doc_module_name":25,"category_name":112,"show_sort_weight":113,"slug":114},8,"Research & Report",30,"research-report",{"id":116,"doc_module":4,"doc_module_name":25,"category_name":117,"show_sort_weight":118,"slug":119},9,"Religion & Spirituality",20,"religion-spirituality",{"id":118,"doc_module":4,"doc_module_name":25,"category_name":121,"show_sort_weight":118,"slug":122},"World Cup","world-cup",{"id":124,"doc_module":4,"doc_module_name":25,"category_name":125,"show_sort_weight":124,"slug":126},10,"Lifestyle","lifestyle",{"id":128,"doc_module":4,"doc_module_name":25,"category_name":129,"show_sort_weight":97,"slug":130},19,"General","general",{"code":4,"msg":82,"data":132},{"doc_id":79,"user_id":133,"nickname":42,"user_avatar":134,"doc_module":4,"category_id":107,"category_name":29,"doc_title":10,"doc_description":12,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":55,"is_deleted":4,"is_public":22,"is_downloadable":22,"audit_status":22,"page_count":140,"language":141,"language_code":8,"site_id":7,"html_lang":8,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":12,"update_tm":145,"read_time":108},1099513958607,"https://ap-avatar.wpscdn.com/avatar/100002390cf8733938c?x-image-process=image/resize,m_fixed,w_180,h_180&k=1778829742770036399","cells  \nArticle  \nSulforaphane Potentiates Gemcitabine-Mediated Anti-Cancer Effects against Intrahepatic Cholangiocarcinoma by Inhibiting HDAC Activity  \nFumimasa Tomooka, Kosuke Kaji *, Norihisa Nishimura , Takahiro Kubo, Satoshi Iwai , Akihiko Shibamoto, Junya Suzuki, Koh Kitagawa , Tadashi Namisaki , Takemi Akahane , Akira Mitoro and Hitoshi Yoshiji  \nCitation: Tomooka, F.; Kaji, K.; Nishimura, N.; Kubo, T.; Iwai, S.; Shibamoto, A.; Suzuki, J.; Kitagawa, K.; Namisaki, T.; Akahane, T.; et al. Sulforaphane Potentiates Gemcitabine-Mediated Anti-Cancer Effects against Intrahepatic Cholangiocarcinoma by Inhibiting HDAC Activity. Cells 2023, 12, 687 . [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)cells12050687  \nAcademic Editor: Nat¡lia Cruz-Martins  \nReceived: 31 January 2023  \nRevised: 19 February 2023  \nAccepted: 20 February 2023  \nPublished: 22 February 2023  \nCopyright: © 2023 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/)) .  \nDepartment of Gastroenterology, Nara Medical University, Kashihara, Nara 634-8521, Japan  \n* Correspondence: [kajik@naramed-u.ac.jp](kajik@naramed-u.ac.jp); Tel.: +81-744-22-3051; Fax: +81-744-24-7122  \nAbstract: Intrahepatic cholangiocarcinoma (iCCA), the second most common primary liver cancer, has high mortality rates because of its limited treatment options and acquired resistance to chemotherapy. Sulforaphane (SFN), a naturally occurring organosulfur compound found in cruciferous vegetables, exhibits multiple therapeutic properties, such as histone deacetylase (HDAC) inhibition and anti-cancer effects. This study assessed the effects of the combination of SFN and gemcitabine (GEM) on human iCCA cell growth. HuCCT-1 and HuH28 cells, representing moderately differentiated and undifferentiated iCCA, respectively, were treated with SFN and/or GEM. SFN concentration dependently reduced total HDAC activity and promoted total histone H3 acetylation in both iCCA cell lines. SFN synergistically augmented the GEM-mediated attenuation of cell viability and proliferation by inducing G2/M cell cycle arrest and apoptosis in both cell lines, as indicated by the cleavage of caspase-3 . SFN also inhibited cancer cell invasion and decreased the expression of pro-angiogenic markers (VEGFA, VEGFR2, HIF-1􀀋, and eNOS) in both iCCA cell lines. Notably, SFN effectively inhibited the GEM-mediated induction of epithelial–mesenchymal transition (EMT) . Axenograft assay demonstrated that SFN and GEM substantially attenuated human iCCA cell-derived tumor growth with decreased Ki67+ proliferative cells and increased TUNEL+ apoptotic cells. The anti-cancer effects of every single agent were markedly augmented by concomitant use. Consistent with the results of in vitro cell cycle analysis, G2/M arrest was indicated by increased p21 and p-Chk2 expression and decreased p-Cdc25C expression in the tumors of SFN-and GEM-treated mice. Moreover, treatment with SFN inhibited CD34-positive neovascularization with decreased VEGF expression and GEM-induced EMT in iCCA-derived xenografted tumors. In conclusion, these results suggest that combination therapy with SFN with GEM is a potential novel option for iCCA treatment.  \nKeywords: chemoresistance; angiogenesis; EMT; cell cycle arrest; apoptosis  \n1. Introduction  \nIntrahepatic cholangiocarcinoma (iCCA) is the second most common hepatic malignancy arising from intrahepatic bile duct epithelium [1] . The prognosis of iCCA is poor because of early local invasion; metastasis to the liver, lymph nodes, and other organs; and insufficient early diagnosis [1,2] . Currently, only a small number of patients with iCCA can undergo curative resection. Meanwhile, the treatment lands","cbCairNanvxJgXsn","https://ap.wps.com/l/cbCairNanvxJgXsn","pdf",4119793,16,"English","# Abstract\n# Introduction\n## Current treatment limitations in iCCA\n## Chemotherapy options and resistance\n## Rationale for targeting HDACs with SFN","[{\"question\":\"Why is iCCA prognosis poor and what drives chemotherapy resistance?\",\"answer\":\"iCCA has poor prognosis due to early local invasion, metastasis, and insufficient early diagnosis. Acquired resistance to chemotherapy limits available treatment options and contributes to high mortality.\"},{\"question\":\"What molecular effects does SFN produce in iCCA cells?\",\"answer\":\"SFN reduces total HDAC activity in a concentration-dependent manner and promotes histone H3 acetylation. It also synergizes with GEM to induce G2/M arrest and apoptosis, indicated by caspase-3 cleavage.\"},{\"question\":\"How does SFN influence angiogenesis and EMT in combination with GEM?\",\"answer\":\"SFN inhibits cancer cell invasion and decreases pro-angiogenic markers such as VEGFA, VEGFR2, HIF-1, and eNOS. It also prevents GEM-mediated induction of epithelial–mesenchymal transition (EMT) and reduces tumor neovascularization markers in vivo.\"}]","Sulforaphane Potentiates Gemcitabine-Mediated Anti-Cancer Effects against Intrahepatic Cholangiocarcinoma - Inhibiting HDAC Activity | PDF",1790249292]