{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T22:56:26Z","timestamp":1789167386755,"version":"build-2803163510"},"reference-count":37,"publisher":"Springer Science and Business Media LLC","issue":"11","license":[{"start":{"date-parts":[[2020,9,8]],"date-time":"2020-09-08T00:00:00Z","timestamp":1599523200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"},{"start":{"date-parts":[[2020,9,8]],"date-time":"2020-09-08T00:00:00Z","timestamp":1599523200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Mol Med"],"published-print":{"date-parts":[[2020,11]]},"DOI":"10.1007\/s00109-020-01977-w","type":"journal-article","created":{"date-parts":[[2020,9,10]],"date-time":"2020-09-10T09:11:41Z","timestamp":1599729101000},"page":"1591-1602","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Targeting X chromosome-linked inhibitor of apoptosis protein in mucoepidermoid carcinoma of the head and neck: A novel therapeutic strategy using nitidine chloride"],"prefix":"10.1007","volume":"98","author":[{"given":"Hye-Jeong","family":"Kwon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyungsil","family":"Yoon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-Youn","family":"Jung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mi Heon","family":"Ryu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung-Hyun","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun-Seon","family":"Yoo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"So-Young","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In-Hyoung","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seong Doo","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5407-2611","authenticated-orcid":false,"given":"Ji-Ae","family":"Shin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung-Dae","family":"Cho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,9,8]]},"reference":[{"issue":"2","key":"1977_CR1","doi-asserted-by":"publisher","first-page":"251","DOI":"10.2174\/187152711794480429","volume":"10","author":"MD Da Rocha","year":"2011","unstructured":"Da Rocha MD, Viegas FP, Campos HC, Nicastro PC, Fossaluzza PC, Fraga CA, Barreiro EJ, Viegas C Jr (2011) The role of natural products in the discovery of new drug candidates for the treatment of neurodegenerative disorders II: Alzheimer\u2019s disease. CNS Neurol Disord Drug Targets 10(2):251\u2013270","journal-title":"CNS Neurol Disord Drug Targets"},{"issue":"9","key":"1977_CR2","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1080\/14786410903417378","volume":"24","author":"SK Shukla","year":"2010","unstructured":"Shukla SK, Gupta S, Ojha SK, Sharma SB (2010) Cardiovascular friendly natural products: a promising approach in the management of CVD. Nat Prod Res 24(9):873\u2013898","journal-title":"Nat Prod Res"},{"issue":"12-13","key":"1977_CR3","first-page":"975","volume":"81","author":"JL Rios","year":"2015","unstructured":"Rios JL, Francini F, Schinella GR (2015) Natural products for the treatment of type 2 diabetes mellitus. Planta Med 81(12-13):975\u2013994","journal-title":"Planta Med"},{"issue":"6","key":"1977_CR4","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1111\/j.1751-7915.2010.00221.x","volume":"4","author":"AL Demain","year":"2011","unstructured":"Demain AL, Vaishnav P (2011) Natural products for cancer chemotherapy. Microb Biotechnol 4(6):687\u2013699","journal-title":"Microb Biotechnol"},{"issue":"12","key":"1977_CR5","doi-asserted-by":"publisher","first-page":"767","DOI":"10.1007\/s12094-007-0138-9","volume":"9","author":"M Gordaliza","year":"2007","unstructured":"Gordaliza M (2007) Natural products as leads to anticancer drugs. Clin Transl Oncol 9(12):767\u2013776","journal-title":"Clin Transl Oncol"},{"key":"1977_CR6","doi-asserted-by":"publisher","first-page":"17109","DOI":"10.1038\/nplants.2017.109","volume":"3","author":"FS Li","year":"2017","unstructured":"Li FS, Weng JK (2017) Demystifying traditional herbal medicine with modern approach. Nature Plants 3:17109","journal-title":"Nature Plants"},{"issue":"1","key":"1977_CR7","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/j.jep.2012.08.041","volume":"144","author":"Z Wang","year":"2012","unstructured":"Wang Z, Jiang W, Zhang Z, Qian M, Du B (2012) Nitidine chloride inhibits LPS-induced inflammatory cytokines production via MAPK and NF-kappaB pathway in RAW 264.7 cells. J Ethnopharmacol 144(1):145\u2013150","journal-title":"J Ethnopharmacol"},{"key":"1977_CR8","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1186\/1475-2875-11-67","volume":"11","author":"J Bouquet","year":"2012","unstructured":"Bouquet J, Rivaud M, Chevalley S, Deharo E, Jullian V, Valentin A (2012) Biological activities of nitidine, a potential anti-malarial lead compound. Malaria J 11:67","journal-title":"Malaria J"},{"issue":"12","key":"1977_CR9","doi-asserted-by":"publisher","first-page":"2862","DOI":"10.1128\/AAC.43.12.2862","volume":"43","author":"M Del Poeta","year":"1999","unstructured":"Del Poeta M, Chen SF, Von Hoff D, Dykstra CC, Wani MC, Manikumar G, Heitman J, Wall ME, Perfect JR (1999) Comparison of in vitro activities of camptothecin and nitidine derivatives against fungal and cancer cells. Antimicrob Agents Chemother 43(12):2862\u20132868","journal-title":"Antimicrob Agents Chemother"},{"issue":"2","key":"1977_CR10","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/j.canlet.2011.09.001","volume":"313","author":"X Pan","year":"2011","unstructured":"Pan X, Han H, Wang L, Yang L, Li R, Li Z, Liu J, Zhao Q, Qian M, Liu M et al (2011) Nitidine chloride inhibits breast cancer cells migration and invasion by suppressing c-Src\/FAK associated signaling pathway. Cancer Lett 313(2):181\u2013191","journal-title":"Cancer Lett"},{"issue":"1","key":"1977_CR11","doi-asserted-by":"publisher","first-page":"60","DOI":"10.2174\/1573406413666170620091543","volume":"14","author":"P Li","year":"2018","unstructured":"Li P, Yan S, Dong X, Li Z, Qiu Y, Ji C, Zhang J, Ji M, Li W, Wang H et al (2018) Cell cycle arrest and apoptosis induction activity of nitidine chloride on acute myeloid leukemia cells. Med Chem 14(1):60\u201366","journal-title":"Med Chem"},{"issue":"53","key":"1977_CR12","doi-asserted-by":"publisher","first-page":"91306","DOI":"10.18632\/oncotarget.20444","volume":"8","author":"LH Kim","year":"2017","unstructured":"Kim LH, Khadka S, Shin JA, Jung JY, Ryu MH, Yu HJ, Lee HN, Jang B, Yang IH, Won DH et al (2017) Nitidine chloride acts as an apoptosis inducer in human oral cancer cells and a nude mouse xenograft model via inhibition of STAT3. Oncotarget 8(53):91306\u201391315","journal-title":"Oncotarget"},{"key":"1977_CR13","doi-asserted-by":"publisher","first-page":"197","DOI":"10.3389\/fonc.2014.00197","volume":"4","author":"P Obexer","year":"2014","unstructured":"Obexer P, Ausserlechner MJ (2014) X-linked inhibitor of apoptosis protein - a critical death resistance regulator and therapeutic target for personalized cancer therapy. Front Oncol 4:197","journal-title":"Front Oncol"},{"issue":"2","key":"1977_CR14","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/j.molcel.2008.03.008","volume":"30","author":"SM Srinivasula","year":"2008","unstructured":"Srinivasula SM, Ashwell JD (2008) IAPs: what\u2019s in a name? Mol Cell 30(2):123\u2013135","journal-title":"Mol Cell"},{"issue":"6","key":"1977_CR15","doi-asserted-by":"publisher","first-page":"872","DOI":"10.1016\/j.ceb.2010.08.025","volume":"22","author":"J Lopez","year":"2010","unstructured":"Lopez J, Meier P (2010) To fight or die - inhibitor of apoptosis proteins at the crossroad of innate immunity and death. Curr Opin Cell Biol 22(6):872\u2013881","journal-title":"Curr Opin Cell Biol"},{"key":"1977_CR16","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1186\/s13014-015-0437-1","volume":"10","author":"L Flanagan","year":"2015","unstructured":"Flanagan L, Kehoe J, Fay J, Bacon O, Lindner AU, Kay EW, Deasy J, Mcnamara DA, Prehn JH (2015) High levels of X-linked inhibitor-of-apoptosis protein (XIAP) are indicative of radio chemotherapy resistance in rectal cancer. Radiat Oncol 10:131","journal-title":"Radiat Oncol"},{"issue":"18","key":"1977_CR17","doi-asserted-by":"publisher","first-page":"4496","DOI":"10.1158\/1078-0432.CCR-10-1664","volume":"16","author":"H Kashkar","year":"2010","unstructured":"Kashkar H (2010) X-linked inhibitor of apoptosis: a chemoresistance factor or a hollow promise. Clin Cancer Res 16(18):4496\u20134502","journal-title":"Clin Cancer Res"},{"issue":"11","key":"1977_CR18","doi-asserted-by":"publisher","first-page":"824","DOI":"10.1002\/ajh.20656","volume":"81","author":"Y Nakagawa","year":"2006","unstructured":"Nakagawa Y, Abe S, Kurata M, Hasegawa M, Yamamoto K, Inoue M, Takemura T, Suzuki K, Kitagawa M (2006) IAP family protein expression correlates with poor outcome of multiple myeloma patients in association with chemotherapy-induced overexpression of multidrug resistance genes. Am J Hematol 81(11):824\u2013831","journal-title":"Am J Hematol"},{"issue":"4","key":"1977_CR19","first-page":"919","volume":"30","author":"Y Mizutani","year":"2007","unstructured":"Mizutani Y, Nakanishi H, Li YN, Matsubara H, Yamamoto K, Sato N, Shiraishi T, Nakamura T, Mikami K, Okihara K et al (2007) Overexpression of XIAP expression in renal cell carcinoma predicts a worse prognosis. Int J Oncol 30(4):919\u2013925","journal-title":"Int J Oncol"},{"issue":"3","key":"1977_CR20","doi-asserted-by":"publisher","first-page":"e31601","DOI":"10.1371\/journal.pone.0031601","volume":"7","author":"XH Yang","year":"2012","unstructured":"Yang XH, Feng ZE, Yan M, Hanada S, Zuo H, Yang CZ, Han ZG, Guo W, Chen WT, Zhang P (2012) XIAP is a predictor of cisplatin-based chemotherapy response and prognosis for patients with advanced head and neck cancer. PLoS One 7(3):e31601","journal-title":"PLoS One"},{"issue":"6","key":"1977_CR21","doi-asserted-by":"publisher","first-page":"1145","DOI":"10.1016\/j.hoc.2015.08.002","volume":"29","author":"CP Rodriguez","year":"2015","unstructured":"Rodriguez CP, Parvathaneni U, Mendez E, Martins RG (2015) Salivary gland malignancies. Hematol Oncol Clin North Am 29(6):1145\u20131157","journal-title":"Hematol Oncol Clin North Am"},{"issue":"6","key":"1977_CR22","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1111\/jphp.12901","volume":"70","author":"S Chen","year":"2018","unstructured":"Chen S, Yang L, Feng J (2018) Nitidine chloride inhibits proliferation and induces apoptosis in ovarian cancer cells by activating the Fas signalling pathway. J Pharm Pharmacol 70(6):778\u2013786","journal-title":"J Pharm Pharmacol"},{"issue":"10","key":"1977_CR23","doi-asserted-by":"publisher","first-page":"10201","DOI":"10.1007\/s13277-014-2327-9","volume":"35","author":"M Sun","year":"2014","unstructured":"Sun M, Zhang N, Wang X, Cai C, Cun J, Li Y, Lv S, Yang Q (2014) Nitidine chloride induces apoptosis, cell cycle arrest, and synergistic cytotoxicity with doxorubicin in breast cancer cells. Tumour Biol 35(10):10201\u201310212","journal-title":"Tumour Biol"},{"key":"1977_CR24","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1016\/j.fct.2014.01.049","volume":"66","author":"Z Fang","year":"2014","unstructured":"Fang Z, Tang Y, Jiao W, Xing Z, Guo Z, Wang W, Xu Z, Liu Z (2014) Nitidine chloride induces apoptosis and inhibits tumor cell proliferation via suppressing ERK signaling pathway in renal cancer. Food Chem Toxicol 66:210\u2013216","journal-title":"Food Chem Toxicol"},{"issue":"2","key":"1977_CR25","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1158\/1535-7163.MCT-11-0648","volume":"11","author":"J Chen","year":"2012","unstructured":"Chen J, Wang J, Lin L, He L, Wu Y, Zhang L, Yi Z, Chen Y, Pang X, Liu M (2012) Inhibition of STAT3 signaling pathway by nitidine chloride suppressed the angiogenesis and growth of human gastric cancer. Mol Cancer Ther 11(2):277\u2013287","journal-title":"Mol Cancer Ther"},{"key":"1977_CR26","doi-asserted-by":"crossref","unstructured":"Yang IH, Jung W, Kim LH, Shin JA, Cho NP, Hong SD, Hong KO, Cho SD (2018) Nitidine chloride represses Mcl-1 protein via lysosomal degradation in oral squamous cell carcinoma. J Oral Pathol Med 47(9):823\u2013829","DOI":"10.1111\/jop.12755"},{"issue":"7","key":"1977_CR27","doi-asserted-by":"publisher","first-page":"E974","DOI":"10.1210\/jc.2014-4356","volume":"100","author":"AR Hussain","year":"2015","unstructured":"Hussain AR, Bu R, Ahmed M, Jehan Z, Beg S, Al-Sobhi S, Al-Dayel F, Siraj AK, Uddin S, Al-Kuraya KS (2015) Role of X-linked inhibitor of apoptosis as a prognostic marker and therapeutic target in papillary thyroid carcinoma. J Clin Endocrinol Metab 100(7):E974\u2013E985","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"1977_CR28","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1186\/s13005-017-0138-0","volume":"13","author":"G Frohwitter","year":"2017","unstructured":"Frohwitter G, Buerger H, Korsching E, Van Diest PJ, Kleinheinz J, Fillies T (2017) Site-specific gene expression patterns in oral cancer. Head Face Med 13(1):6","journal-title":"Head Face Med"},{"issue":"2","key":"1977_CR29","first-page":"EC01","volume":"9","author":"BB Bagulkar","year":"2015","unstructured":"Bagulkar BB, Gawande M, Chaudhary M, Gadbail AR, Patil S, Bagulkar S (2015) XIAP and Ki-67: A correlation between antiapoptotic and proliferative marker expression in benign and malignant tumours of salivary gland: an immunohistochemical study. J Clin Diagn Res 9(2):EC01\u2013EC04","journal-title":"J Clin Diagn Res"},{"key":"1977_CR30","doi-asserted-by":"publisher","first-page":"587","DOI":"10.12688\/f1000research.10625.1","volume":"6","author":"D Finlay","year":"2017","unstructured":"Finlay D, Teriete P, Vamos M, Cosford NDP, Vuori K (2017) Inducing death in tumor cells: roles of the inhibitor of apoptosis proteins. F1000Research 6:587","journal-title":"F1000Research"},{"issue":"1","key":"1977_CR31","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/S1535-6108(03)00332-5","volume":"5","author":"AD Schimmer","year":"2004","unstructured":"Schimmer AD, Welsh K, Pinilla C, Wang Z, Krajewska M, Bonneau MJ, Pedersen IM, Kitada S, Scott FL, Bailly-Maitre B et al (2004) Small-molecule antagonists of apoptosis suppressor XIAP exhibit broad antitumor activity. Cancer Cell 5(1):25\u201335","journal-title":"Cancer Cell"},{"issue":"5","key":"1977_CR32","doi-asserted-by":"publisher","first-page":"5993","DOI":"10.18632\/oncotarget.23202","volume":"9","author":"VV Gowda Saralamma","year":"2018","unstructured":"Gowda Saralamma VV, Lee HJ, Raha S, Lee WS, Kim EH, Lee SJ, Heo JD, Won C, Kang CK, Kim GS (2018) Inhibition of IAP\u2019s and activation of p53 leads to caspase-dependent apoptosis in gastric cancer cells treated with Scutellarein. Oncotarget 9(5):5993\u20136006","journal-title":"Oncotarget"},{"key":"1977_CR33","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1016\/j.biopha.2018.02.019","volume":"100","author":"T Takeda","year":"2018","unstructured":"Takeda T, Tsubaki M, Tomonari Y, Kawashima K, Itoh T, Imano M, Satou T, Nishida S (2018) Bavachin induces the apoptosis of multiple myeloma cell lines by inhibiting the activation of nuclear factor kappa B and signal transducer and activator of transcription 3. Biomed Pharmacother 100:486\u2013494","journal-title":"Biomed Pharmacother"},{"issue":"11","key":"1977_CR34","doi-asserted-by":"publisher","first-page":"2371","DOI":"10.1002\/tox.22450","volume":"32","author":"YJ Lee","year":"2017","unstructured":"Lee YJ, Park BS, Park HR, Yu SB, Kang HM, Kim IR (2017) XIAP inhibitor embelin induces autophagic and apoptotic cell death in human oral squamous cell carcinoma cells. Environ Toxicol 32(11):2371\u20132378","journal-title":"Environ Toxicol"},{"issue":"1","key":"1977_CR35","doi-asserted-by":"publisher","first-page":"79","DOI":"10.3892\/ijmm.2013.1358","volume":"32","author":"J Liao","year":"2013","unstructured":"Liao J, Xu T, Zheng JX, Lin JM, Cai QY, Yu DB, Peng J (2013) Nitidine chloride inhibits hepatocellular carcinoma cell growth in vivo through the suppression of the JAK1\/STAT3 signaling pathway. Int J Mol Med 32(1):79\u201384","journal-title":"Int J Mol Med"},{"issue":"9","key":"1977_CR36","doi-asserted-by":"publisher","first-page":"1411","DOI":"10.1091\/mbc.e13-11-0664","volume":"25","author":"N Hiramatsu","year":"2014","unstructured":"Hiramatsu N, Messah C, Han J, Lavail MM, Kaufman RJ, Lin JH (2014) Translational and posttranslational regulation of XIAP by eIF2alpha and ATF4 promotes ER stress-induced cell death during the unfolded protein response. Mol Biol Cell 25(9):1411\u20131420","journal-title":"Mol Biol Cell"},{"issue":"8","key":"1977_CR37","doi-asserted-by":"publisher","first-page":"e0182433","DOI":"10.1371\/journal.pone.0182433","volume":"12","author":"J Cai","year":"2017","unstructured":"Cai J, Wang D, Bai ZG, Yin J, Zhang J, Zhang ZT (2017) The long noncoding RNA XIAP-AS1 promotes XIAP transcription by XIAP-AS1 interacting with Sp1 in gastric cancer cells. PLoS One 12(8):e0182433","journal-title":"PLoS One"}],"container-title":["Journal of Molecular Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00109-020-01977-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00109-020-01977-w\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00109-020-01977-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,7]],"date-time":"2021-09-07T23:07:49Z","timestamp":1631056069000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00109-020-01977-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,8]]},"references-count":37,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2020,11]]}},"alternative-id":["1977"],"URL":"https:\/\/doi.org\/10.1007\/s00109-020-01977-w","relation":{},"ISSN":["0946-2716","1432-1440"],"issn-type":[{"value":"0946-2716","type":"print"},{"value":"1432-1440","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,8]]},"assertion":[{"value":"29 October 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 August 2020","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 September 2020","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 September 2020","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Clinical samples were approved by the Institutional Review Board of Pusan National University Yangsan Hospital (IRB approval number: PNUDH-2018-016) and animal study was in accordance with the Institutional Animal Care and Use Committee (IACUC) guidelines approved by Kongju National University (IACUC approval number: KNU2018-4).","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"The authors declare that they have no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}