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The study evaluates how cytochrome P450 enzymes (CYPs) contribute to doxorubicin (DOX) resistance and how KCa1.1 inhibition counteracts it in cancer spheroid models. CYP3A4 is induced by spheroid formation and suppressed by KCa1.1 inhibition via transcriptional repression of CEBPB downstream of Nrf2. DOX resistance is reversed through CYP3A4 knockdown and ketoconazole treatment, with Akt–Nrf2–CEBPB axis mediating the effect.",{"@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":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/down-regulation-of-cyp3a4-by-the-kca-11-inhibition-is-responsible-for-overcoming-resistance-to-doxorubicin-in-cancer-spheroid-models/381831/",{"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/down-regulation-of-cyp3a4-by-the-kca-11-inhibition-is-responsible-for-overcoming-resistance-to-doxorubicin-in-cancer-spheroid-models/381831.png","ImageObject",300,407,{"name":92,"@type":93},"Jasmine","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-29","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":52},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"How does KCa1.1 influence DOX resistance in cancer spheroid models?","Question",{"text":112,"@type":113},"KCa1.1 inhibition overcomes DOX resistance by suppressing CYP3A4-related pathways, including transcriptional repression of CEBPB downstream of Nrf2.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"Which CYP isoform is highlighted as responsible for acquiring DOX resistance?",{"text":117,"@type":113},"CYP3A4 is described as up-regulated by spheroid formation and significantly suppressed by KCa1.1 inhibition, making it responsible for DOX resistance acquisition in these models.",{"name":119,"@type":110,"acceptedAnswer":120},"What experimental strategies are used to overcome DOX resistance?",{"text":121,"@type":113},"DOX resistance is overcome by siRNA-mediated inhibition of CYP3A4 and by treatment with ketoconazole, a potent CYP3A4 inhibitor.","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},381831,1790467871,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":52,"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},2336478487870,"https://ap-avatar.wpscdn.com/davatar_085a072bc5b1113ac321206ff7593b45","Article  \nDown-Regulation of CYP3A4 by the KCa 1.1 Inhibition Is Responsible for Overcoming Resistance to Doxorubicin in Cancer Spheroid Models  \nSusumu Ohya *, Junko Kajikuri , Hiroaki Kito and Miki Matsui  \nCitation: Ohya, S.; Kajikuri, J.; Kito, H.; Matsui, M. Down-Regulation of CYP3A4 by the KCa 1.1 Inhibition Is Responsible for Overcoming Resistance to Doxorubicin in Cancer Spheroid Models. Int. J. Mol. Sci. 2023, 24, 15672. [https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.3390/ijms242115672](10.3390/ijms242115672)  \nAcademic Editor: Bernard Haendler  \nReceived: 10 October 2023  \nRevised: 26 October 2023  \nAccepted: 26 October 2023  \nPublished: 27 October 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 Pharmacology, Graduate School of Medical Sciences, Nagoya City University,  \nNagoya 467-8601, Japan; [kajikuri@med.nagoya-cu.ac.jp](kajikuri@med.nagoya-cu.ac.jp) (J.K.); [kito@med.nagoya-cu.ac.jp](kito@med.nagoya-cu.ac.jp) (H.K.);  \n[miki.matsui.4238@gmail.com](miki.matsui.4238@gmail.com) (M.M.)  \n* Correspondence: [sohya@med.nagoya-cu.ac.jp](sohya@med.nagoya-cu.ac.jp); Tel.: +81-52-853-8149  \nAbstract: The large-conductance Ca2+-activated K+ channel, K Ca1. 1, plays a pivotal role in cancer progression, metastasis, and the acquisition of chemoresistance. Previous studies indicated that the pharmacological inhibition of KCa 1.1 overcame resistance to doxorubicin (DOX) by down-regulating multidrug resistance-associated proteins in the three-dimensional spheroid models of human prostate cancer LNCaP, osteosarcoma MG-63, and chondrosarcoma SW-1353 cells. Investigations have recently focused on the critical roles of intratumoral, drug-metabolizing cytochrome P450 enzymes (CYPs) in chemoresistance. In the present study, we examined the involvement of CYPs in the acquisition of DOX resistance and its overcoming by inhibiting KCa 1.1 in cancer spheroid models. Among the CYP isoforms involved in DOX metabolism, CYP3A4 was up-regulated by spheroid formation and significantly suppressed by the inhibition of KCa 1.1 through the transcriptional repression of CCAAT/enhancer-binding protein, CEBPB, which is a downstream transcription factor of the Nrf2 signaling pathway. DOX resistance was overcome by the siRNA-mediated inhibition of CYP3A4 and treatment with the potent CYP3A4 inhibitor, ketoconazole, in cancer spheroid models. The phosphorylation levels of Akt were significantly reduced by inhibiting KCa 1.1 in cancer spheroid models, and K Ca1.1-induced down-regulation of CYP3A4 was reversed by the treatment with Akt and Nrf2 activators. Collectively, the present results indicate that the up-regulation of CYP3A4 is responsible for the acquisition of DOX resistance in cancer spheroid models, and the inhibition of K Ca1.1 overcame DOX resistance by repressing CYP3A4 transcription mainly through the Akt-Nrf2-CEBPB axis.  \nKeywords: cancer spheroid; doxorubicin resistance; Ca2+-activated K+ channel; K Ca1. 1; Akt-Nrf2; CYP3A4  \n1. Introduction  \nThree-dimensional (3D) cancer spheroid models using ultra-low attachment plates and dishes form spherical self-assembled aggregates of cancer cells and are a valuable tool for examining the tumor microenvironment (TME) in solid cancers with the characteristics of cancer stem cells (CSCs), such as a high metastatic capacity and chemoresistance [1] . Recent studies indicated the essential role of K+ channels in cancer cell proliferation, invasion, migration, and metastasis [2,3] . Among Ca2+-activated K+ channel superfamily members (large-conductance K Ca1.1, small-conductance K Ca2.1–2.3, and intermediateconductance K Ca3.1), KCa 1.1, encoded by KCNMA1, contribut","cbCaihp0mPbJKZj6","https://ap.wps.com/l/cbCaihp0mPbJKZj6","pdf",6075043,17,"English","# Abstract\n# Keywords\n# 1. Introduction\n## 3D cancer spheroid models and K+ channel roles\n## CYPs and their link to drug metabolism and resistance","[{\"question\":\"How does KCa1.1 influence DOX resistance in cancer spheroid models?\",\"answer\":\"KCa1.1 inhibition overcomes DOX resistance by suppressing CYP3A4-related pathways, including transcriptional repression of CEBPB downstream of Nrf2.\"},{\"question\":\"Which CYP isoform is highlighted as responsible for acquiring DOX resistance?\",\"answer\":\"CYP3A4 is described as up-regulated by spheroid formation and significantly suppressed by KCa1.1 inhibition, making it responsible for DOX resistance acquisition in these models.\"},{\"question\":\"What experimental strategies are used to overcome DOX resistance?\",\"answer\":\"DOX resistance is overcome by siRNA-mediated inhibition of CYP3A4 and by treatment with ketoconazole, a potent CYP3A4 inhibitor.\"}]","Down-Regulation of CYP3A4 by the KCa 1.1 Inhibition Is Responsible for Overcoming Resistance to Doxorubicin in Cancer Spheroid Models | PDF",1790247381,43]