{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T18:27:34Z","timestamp":1776364054459,"version":"3.51.2"},"reference-count":38,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2023,9,1]],"date-time":"2023-09-01T00:00:00Z","timestamp":1693526400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100007452","name":"Wu Jieping Medical Foundation","doi-asserted-by":"publisher","award":["320.6750.16223"],"award-info":[{"award-number":["320.6750.16223"]}],"id":[{"id":"10.13039\/100007452","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>Regorafenib is an oral multi-kinase inhibitor approved for various metastatic\/advanced cancers, and has been investigated in clinical trials in many other tumour entities. The purpose of this study was to evaluate the therapeutic potential of regorafenib for nasopharyngeal carcinoma (NPC).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Cellular proliferation, survival, apoptosis and colony formation assays were performed and combination index was determined. NPC xenograft tumour models were established. In vitro and In vivo angiogenesis assays were performed.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Key findings<\/jats:title>\n                  <jats:p>Regorafenib is effective against a panel of NPC cell lines regardless of cellular origin and genetic profiling while sparing normal nasal epithelial cells. The predominant inhibitory effects of regorafenib in NPC are anchorage-dependent and anchorage-independent growth rather than survival. Apart from tumour cells, regorafenib potently inhibits angiogenesis. Mechanistically, regorafenib inhibits multiple oncogenic pathways including Raf\/Erk\/Mek and PI3K\/Akt\/mTOR. Regorafenib decreases Bcl-2 but not Mcl-1 level in NPC cells. The in vitro observations are evident in in vivo NPC xenograft mouse model. The combination of Mcl-1 inhibitor with regorafenib is synergistic in inhibiting NPC growth without causing systemic toxicity in mice.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Our findings also support further clinical investigation of regorafenib and Mcl-1 inhibitor for NPC treatment.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jpp\/rgad034","type":"journal-article","created":{"date-parts":[[2023,5,3]],"date-time":"2023-05-03T13:50:19Z","timestamp":1683121819000},"page":"1177-1185","source":"Crossref","is-referenced-by-count":1,"title":["Regorafenib inhibits growth, survival and angiogenesis in nasopharyngeal carcinoma and is synergistic with Mcl-1 inhibitor"],"prefix":"10.1093","volume":"75","author":[{"given":"Jiangping","family":"Li","sequence":"first","affiliation":[{"name":"Department of Otolaryngology & Head and Neck Surgery, Renmin Hospital of Wuhan University , Wuhan, Hubei 430060 ,","place":["People\u2019s Republic of China"]},{"name":"Department of Otolaryngology & Head and Neck Surgery, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science , Xiangyang, Hubei 441021 ,","place":["People\u2019s Republic of China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6499-0280","authenticated-orcid":false,"given":"Qingquan","family":"Hua","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology & Head and Neck Surgery, Renmin Hospital of Wuhan University , Wuhan, Hubei 430060 ,","place":["People\u2019s Republic of China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2023,9,1]]},"reference":[{"key":"2024103012283027900_CIT0001","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1038\/s41571-021-00524-x","article-title":"Nasopharyngeal carcinoma: an evolving paradigm","volume":"18","author":"Wong","year":"2021","journal-title":"Nat Rev Clin Oncol"},{"key":"2024103012283027900_CIT0002","doi-asserted-by":"crossref","first-page":"635737","DOI":"10.3389\/fonc.2021.635737","article-title":"Nasopharyngeal carcinoma: clinical achievements and considerations among treatment options","volume":"11","author":"Liu","year":"2021","journal-title":"Front Oncol"},{"key":"2024103012283027900_CIT0003","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/s41392-020-00340-2","article-title":"Advances in targeted therapy mainly based on signal pathways for nasopharyngeal carcinoma","volume":"5","author":"Kang","year":"2020","journal-title":"Signal Transduct Target Ther"},{"key":"2024103012283027900_CIT0004","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1080\/13543784.2017.1324568","article-title":"Investigational drugs for nasopharyngeal carcinoma","volume":"26","author":"Ma","year":"2017","journal-title":"Expert Opin Investig Drugs"},{"key":"2024103012283027900_CIT0005","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1002\/ijc.25864","article-title":"Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity","volume":"129","author":"Wilhelm","year":"2011","journal-title":"Int J Cancer"},{"key":"2024103012283027900_CIT0006","doi-asserted-by":"crossref","first-page":"1941","DOI":"10.1080\/14656566.2018.1534956","article-title":"Regorafenib: a promising treatment for hepatocellular carcinoma","volume":"19","author":"Cerrito","year":"2018","journal-title":"Expert Opin Pharmacother"},{"key":"2024103012283027900_CIT0007","doi-asserted-by":"crossref","first-page":"101912","DOI":"10.1016\/j.ctrv.2019.101912","article-title":"Molecular insight of regorafenib treatment for colorectal cancer","volume":"81","author":"Arai","year":"2019","journal-title":"Cancer Treat Rev"},{"key":"2024103012283027900_CIT0008","doi-asserted-by":"crossref","first-page":"4530","DOI":"10.1158\/1078-0432.CCR-18-2840","article-title":"Regorafenib promotes antitumor immunity via inhibiting PD-L1 and IDO1 expression in Melanoma","volume":"25","author":"Wu","year":"2019","journal-title":"Clin Cancer Res"},{"key":"2024103012283027900_CIT0009","doi-asserted-by":"crossref","first-page":"e0142612","DOI":"10.1371\/journal.pone.0142612","article-title":"Regorafenib: antitumor activity upon mono and combination therapy in preclinical pediatric malignancy models","volume":"10","author":"Daudigeos-Dubus","year":"2015","journal-title":"PLoS One"},{"key":"2024103012283027900_CIT0010","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1007\/s11912-013-0292-x","article-title":"Regorafenib (BAY 73-4506): stromal and oncogenic multikinase inhibitor with potential activity in renal cell carcinoma","volume":"15","author":"Zaki","year":"2013","journal-title":"Curr Oncol Rep"},{"key":"2024103012283027900_CIT0011","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1186\/s13046-021-02043-0","article-title":"Regorafenib enhances anti-PD1 immunotherapy efficacy in murine colorectal cancers and their combination prevents tumor regrowth","volume":"40","author":"Doleschel","year":"2021","journal-title":"J Exp Clin Cancer Res"},{"key":"2024103012283027900_CIT0012","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1002\/hep.30889","article-title":"Dual programmed death receptor-1 and vascular endothelial growth factor receptor-2 blockade promotes vascular normalization and enhances antitumor immune responses in hepatocellular carcinoma","volume":"71","author":"Shigeta","year":"2020","journal-title":"Hepatology"},{"key":"2024103012283027900_CIT0013","doi-asserted-by":"crossref","first-page":"174688","DOI":"10.1016\/j.ejphar.2021.174688","article-title":"Preclinical evaluation of the dual mTORC1\/2 inhibitor sapanisertib in combination with cisplatin in nasopharyngeal carcinoma","volume":"915","author":"Zhang","year":"2022","journal-title":"Eur J Pharmacol"},{"key":"2024103012283027900_CIT0014","doi-asserted-by":"crossref","first-page":"1661","DOI":"10.3892\/or.2014.3376","article-title":"Hotspot mutations in common oncogenes are infrequent in nasopharyngeal carcinoma","volume":"32","author":"Jiang","year":"2014","journal-title":"Oncol Rep"},{"key":"2024103012283027900_CIT0015","doi-asserted-by":"crossref","first-page":"10528","DOI":"10.1073\/pnas.0504367102","article-title":"Proliferation and invasion: plasticity in tumor cells","volume":"102","author":"Gao","year":"2005","journal-title":"Proc Natl Acad Sci USA"},{"key":"2024103012283027900_CIT0016","doi-asserted-by":"crossref","first-page":"2796","DOI":"10.1038\/onc.2009.139","article-title":"Anchorage-independent cell growth signature identifies tumors with metastatic potential","volume":"28","author":"Mori","year":"2009","journal-title":"Oncogene"},{"key":"2024103012283027900_CIT0017","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.addr.2014.06.005","article-title":"Matrigel: from discovery and ECM mimicry to assays and models for cancer research","volume":"79-80","author":"Benton","year":"2014","journal-title":"Adv Drug Deliv Rev"},{"key":"2024103012283027900_CIT0018","doi-asserted-by":"crossref","first-page":"3568","DOI":"10.1200\/JCO.2005.02.147","article-title":"Multicenter, phase II study of cetuximab in combination with carboplatin in patients with recurrent or metastatic nasopharyngeal carcinoma","volume":"23","author":"Chan","year":"2005","journal-title":"J Clin Oncol"},{"key":"2024103012283027900_CIT0019","doi-asserted-by":"crossref","first-page":"2820","DOI":"10.1093\/annonc\/mdx439","article-title":"A randomized, phase 2 study of cetuximab plus cisplatin with or without paclitaxel for the first-line treatment of patients with recurrent and\/or metastatic squamous cell carcinoma of the head and neck","volume":"28","author":"Bossi","year":"2017","journal-title":"Ann Oncol"},{"key":"2024103012283027900_CIT0020","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1111\/1440-1681.13649","article-title":"Inhibition of mTOR by temsirolimus overcomes radio-resistance in nasopharyngeal carcinoma","volume":"49","author":"Huang","year":"2022","journal-title":"Clin Exp Pharmacol Physiol"},{"key":"2024103012283027900_CIT0021","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1016\/j.bbrc.2019.04.053","article-title":"Ribavirin sensitizes nasopharyngeal carcinoma to 5-fluorouracil through suppressing 5-fluorouracil-induced ERK-dependent-eIF4E activation","volume":"513","author":"Hu","year":"2019","journal-title":"Biochem Biophys Res Commun"},{"key":"2024103012283027900_CIT0022","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1186\/s13046-015-0243-5","article-title":"Antitumor activity of the multikinase inhibitor regorafenib in patient-derived xenograft models of gastric cancer","volume":"34","author":"Huynh","year":"2015","journal-title":"J Exp Clin Cancer Res"},{"key":"2024103012283027900_CIT0023","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1038\/s41416-020-0905-8","article-title":"Regorafenib is effective against neuroblastoma in vitro and in vivo and inhibits the RAS\/MAPK, PI3K\/Akt\/mTOR and Fos\/Jun pathways","volume":"123","author":"Subramonian","year":"2020","journal-title":"Br J Cancer"},{"key":"2024103012283027900_CIT0024","doi-asserted-by":"crossref","first-page":"2569","DOI":"10.21873\/invivo.12539","article-title":"Induction of apoptosis and inhibition of EGFR\/NF-kappaB signaling are associated with regorafenib-sensitized non-small cell lung cancer to cisplatin","volume":"35","author":"Wu","year":"2021","journal-title":"In vivo"},{"key":"2024103012283027900_CIT0025","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1007\/s00210-017-1412-1","article-title":"A marginal anticancer effect of regorafenib on pancreatic carcinoma cells in vitro, ex vivo, and in vivo","volume":"390","author":"Mayer","year":"2017","journal-title":"Naunyn Schmiedebergs Arch Pharmacol"},{"key":"2024103012283027900_CIT0026","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1080\/09553002.2020.1730012","article-title":"Regorafenib sensitizes human breast cancer cells to radiation by inhibiting multiple kinases and inducing DNA damage","volume":"97","author":"Mehta","year":"2021","journal-title":"Int J Radiat Biol"},{"key":"2024103012283027900_CIT0027","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1007\/s11523-014-0333-x","article-title":"Regorafenib as a single-agent in the treatment of patients with gastrointestinal tumors: an overview for pharmacists","volume":"10","author":"Rey","year":"2015","journal-title":"Targeted oncology"},{"key":"2024103012283027900_CIT0028","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/S0140-6736(12)61900-X","article-title":"Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial","volume":"381","author":"Grothey","year":"2013","journal-title":"Lancet"},{"key":"2024103012283027900_CIT0029","doi-asserted-by":"crossref","first-page":"36220","DOI":"10.18632\/oncotarget.26333","article-title":"The multikinase inhibitor regorafenib decreases angiogenesis and improves portal hypertension","volume":"9","author":"Uschner","year":"2018","journal-title":"Oncotarget"},{"key":"2024103012283027900_CIT0030","doi-asserted-by":"crossref","first-page":"2981","DOI":"10.1007\/s11030-022-10406-8","article-title":"A patent review on efficient strategies for the total synthesis of pazopanib, regorafenib and lenvatinib as novel anti-angiogenesis receptor tyrosine kinase inhibitors for cancer therapy","volume":"26","author":"Shiri","year":"2022","journal-title":"Mol Divers"},{"key":"2024103012283027900_CIT0031","doi-asserted-by":"crossref","first-page":"e0016571","DOI":"10.1136\/jitc-2020-001657","article-title":"Regorafenib enhances antitumor immunity via inhibition of p38 kinase\/Creb1\/Klf4 axis in tumor-associated macrophages","volume":"9","author":"Ou","year":"2021","journal-title":"J ImmunoTher Cancer"},{"key":"2024103012283027900_CIT0032","doi-asserted-by":"crossref","first-page":"e116","DOI":"10.3324\/haematol.2018.212308","article-title":"Preclinical evaluation of the simultaneous inhibition of MCL-1 and BCL-2 with the combination of S63845 and venetoclax in multiple myeloma","volume":"105","author":"Algarin","year":"2020","journal-title":"Haematologica"},{"key":"2024103012283027900_CIT0033","doi-asserted-by":"crossref","first-page":"8098","DOI":"10.7150\/thno.45363","article-title":"Mcl-1 inhibition overcomes intrinsic and acquired regorafenib resistance in colorectal cancer","volume":"10","author":"Song","year":"2020","journal-title":"Theranostics"},{"key":"2024103012283027900_CIT0034","doi-asserted-by":"crossref","first-page":"3472","DOI":"10.1158\/1078-0432.CCR-13-2944","article-title":"Regorafenib inhibits colorectal tumor growth through PUMA-mediated apoptosis","volume":"20","author":"Chen","year":"2014","journal-title":"Clin Cancer Res"},{"key":"2024103012283027900_CIT0035","doi-asserted-by":"crossref","first-page":"694","DOI":"10.3389\/fonc.2020.00694","article-title":"Targeting SphK2 reverses acquired resistance of regorafenib in hepatocellular carcinoma","volume":"10","author":"Shi","year":"2020","journal-title":"Front Oncol"},{"key":"2024103012283027900_CIT0036","doi-asserted-by":"crossref","first-page":"639779","DOI":"10.3389\/fcell.2021.639779","article-title":"Changes in Wnt and TGF-beta signaling mediate the development of regorafenib resistance in hepatocellular carcinoma cell line HuH7","volume":"9","author":"Karabicici","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"2024103012283027900_CIT0037","doi-asserted-by":"crossref","first-page":"3766","DOI":"10.1200\/JCO.2006.10.2871","article-title":"Phase II trial of sorafenib in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or nasopharyngeal carcinoma","volume":"25","author":"Elser","year":"2007","journal-title":"J Clin Oncol"},{"key":"2024103012283027900_CIT0038","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1093\/annonc\/mds581","article-title":"Phase II study of sorafenib in combination with cisplatin and 5-fluorouracil to treat recurrent or metastatic nasopharyngeal carcinoma","volume":"24","author":"Xue","year":"2013","journal-title":"Ann Oncol"}],"container-title":["Journal of Pharmacy and Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jpp\/article-pdf\/75\/9\/1177\/60220237\/rgad034.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jpp\/article-pdf\/75\/9\/1177\/60220237\/rgad034.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,30]],"date-time":"2024-10-30T17:24:55Z","timestamp":1730309095000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jpp\/article\/75\/9\/1177\/7150659"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,1]]},"references-count":38,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2023,9,1]]},"published-print":{"date-parts":[[2023,9,1]]}},"URL":"https:\/\/doi.org\/10.1093\/jpp\/rgad034","relation":{},"ISSN":["0022-3573","2042-7158"],"issn-type":[{"value":"0022-3573","type":"print"},{"value":"2042-7158","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,9,1]]},"published":{"date-parts":[[2023,9,1]]}}}