{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T11:06:37Z","timestamp":1791111997114,"version":"4.1.0"},"reference-count":53,"publisher":"Elsevier BV","issue":"11","license":[{"start":{"date-parts":[[2012,11,1]],"date-time":"2012-11-01T00:00:00Z","timestamp":1351728000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2012,11,1]],"date-time":"2012-11-01T00:00:00Z","timestamp":1351728000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Science Foundation of China","doi-asserted-by":"crossref","award":["81072645"],"award-info":[{"award-number":["81072645"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"the Ministry of Science and Technology of China","award":["2009ZX09302-004"],"award-info":[{"award-number":["2009ZX09302-004"]}]}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["The International Journal of Biochemistry & Cell Biology"],"published-print":{"date-parts":[[2012,11]]},"DOI":"10.1016\/j.biocel.2012.06.028","type":"journal-article","created":{"date-parts":[[2012,6,27]],"date-time":"2012-06-27T14:16:33Z","timestamp":1340806593000},"page":"1813-1824","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":101,"title":["Cardiac glycosides induce autophagy in human non-small cell lung cancer cells through regulation of dual signaling pathways"],"prefix":"10.1016","volume":"44","author":[{"given":"Yan","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-Jia","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dian-Dong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue-Jun","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu-Yi","family":"Si","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong-Guang","family":"Shao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.biocel.2012.06.028_bib0005","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1002\/bies.20085","article-title":"The PARP superfamily","volume":"26","author":"Ame","year":"2004","journal-title":"Bioessays"},{"key":"10.1016\/j.biocel.2012.06.028_bib0010","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1124\/mol.106.033167","article-title":"Evidence that curcumin suppresses the growth of malignant gliomas in vitro and in vivo through induction of autophagy: role of Akt and extracellular signal-regulated kinase signaling pathways","volume":"72","author":"Aoki","year":"2007","journal-title":"Molecular Pharmacology"},{"key":"10.1016\/j.biocel.2012.06.028_bib0015","doi-asserted-by":"crossref","first-page":"472","DOI":"10.4161\/auto.5.4.7759","article-title":"Combination treatment with arsenic trioxide and irradiation enhances autophagic effects in U118-MG cells through increased mitotic arrest and regulation of PI3K\/Akt and ERK1\/2 signaling pathways","volume":"5","author":"Chiu","year":"2009","journal-title":"Autophagy"},{"key":"10.1016\/j.biocel.2012.06.028_bib0020","doi-asserted-by":"crossref","first-page":"2950","DOI":"10.1038\/sj.onc.1207558","article-title":"Death receptors in chemotherapy and cancer","volume":"23","author":"Debatin","year":"2004","journal-title":"Oncogene"},{"key":"10.1016\/j.biocel.2012.06.028_bib0025","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1093\/carcin\/bgi214","article-title":"Inhibition of Akt signaling and enhanced ERK1\/2 activity are involved in induction of macroautophagy by triterpenoid B-group soyasaponins in colon cancer cells","volume":"27","author":"Ellington","year":"2006","journal-title":"Carcinogenesis"},{"key":"10.1016\/j.biocel.2012.06.028_bib0030","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1634\/theoncologist.9-2-232","article-title":"Highlights from the tenth world conference on lung cancer","volume":"9","author":"Evans","year":"2004","journal-title":"Oncologist"},{"key":"10.1016\/j.biocel.2012.06.028_bib0035","doi-asserted-by":"crossref","first-page":"5867","DOI":"10.1158\/0008-5472.CAN-05-3544","article-title":"Cardiac glycosides initiate Apo2L\/TRAIL-induced apoptosis in non-small cell lung cancer cells by up-regulation of death receptors 4 and 5","volume":"66","author":"Frese","year":"2006","journal-title":"Cancer Research"},{"key":"10.1016\/j.biocel.2012.06.028_bib0040","doi-asserted-by":"crossref","first-page":"78","DOI":"10.2174\/156652408783769616","article-title":"To die or not to die: that is the autophagic question","volume":"8","author":"Galluzzi","year":"2008","journal-title":"Current Molecular Medicine"},{"key":"10.1016\/j.biocel.2012.06.028_bib0045","doi-asserted-by":"crossref","first-page":"4262","DOI":"10.1182\/blood-2010-02-269837","article-title":"The LKB1\/AMPK signaling pathway has tumor suppressor activity in acute myeloid leukemia through the repression of mTOR-dependent oncogenic mRNA translation","volume":"116","author":"Green","year":"2010","journal-title":"Blood"},{"key":"10.1016\/j.biocel.2012.06.028_bib0050","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.molcel.2008.03.003","article-title":"AMPK phosphorylation of raptor mediates a metabolic checkpoint","volume":"30","author":"Gwinn","year":"2008","journal-title":"Molecular Cell"},{"key":"10.1016\/j.biocel.2012.06.028_bib0055","doi-asserted-by":"crossref","first-page":"1926","DOI":"10.1101\/gad.1212704","article-title":"Upstream and downstream of mTOR","volume":"18","author":"Hay","year":"2004","journal-title":"Genes & Development"},{"key":"10.1016\/j.biocel.2012.06.028_bib0060","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/1741-7007-9-38","article-title":"Concurrent detection of autolysosome formation and lysosomal degradation by flow cytometry in a high-content screen for inducers of autophagy","volume":"9","author":"Hundeshagen","year":"2011","journal-title":"BMC Biology"},{"key":"10.1016\/j.biocel.2012.06.028_bib0065","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1038\/ncb839","article-title":"TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling","volume":"4","author":"Inoki","year":"2002","journal-title":"Nature Cell Biology"},{"key":"10.1016\/j.biocel.2012.06.028_bib0070","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/S0092-8674(03)00929-2","article-title":"TSC2 mediates cellular energy response to control cell growth and survival","volume":"115","author":"Inoki","year":"2003","journal-title":"Cell"},{"key":"10.1016\/j.biocel.2012.06.028_bib0075","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1038\/nrclinonc.2011.71","article-title":"Autophagy as a target for anticancer therapy","volume":"8","author":"Janku","year":"2011","journal-title":"Nature Reviews Clinical Oncology"},{"key":"10.1016\/j.biocel.2012.06.028_bib0080","first-page":"69","article-title":"Global cancer statistics","volume":"61","author":"Jemal","year":"2011","journal-title":"CA Cancer Journal for Clinicians"},{"key":"10.1016\/j.biocel.2012.06.028_bib0085","doi-asserted-by":"crossref","first-page":"4139","DOI":"10.1242\/jcs.114.23.4139","article-title":"The p53 functional circuit","volume":"114","author":"Jin","year":"2001","journal-title":"Journal of Cell Science"},{"key":"10.1016\/j.biocel.2012.06.028_bib0090","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1097\/00001813-200106000-00009","article-title":"Cytotoxicity of digitoxin and related cardiac glycosides in human tumor cells","volume":"12","author":"Johansson","year":"2001","journal-title":"Anticancer Drugs"},{"key":"10.1016\/j.biocel.2012.06.028_bib0095","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.bcp.2009.01.018","article-title":"UNBS1450 from Calotropis procera as a regulator of signaling pathways involved in proliferation and cell death","volume":"78","author":"Juncker","year":"2009","journal-title":"Biochemical Pharmacology"},{"key":"10.1016\/j.biocel.2012.06.028_bib0100","doi-asserted-by":"crossref","first-page":"5720","DOI":"10.1093\/emboj\/19.21.5720","article-title":"LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing","volume":"19","author":"Kabeya","year":"2000","journal-title":"EMBO Journal"},{"key":"10.1016\/j.biocel.2012.06.028_bib0105","first-page":"5645","article-title":"Activated mammalian target of rapamycin pathway in the pathogenesis of tuberous sclerosis complex renal tumors","volume":"62","author":"Kenerson","year":"2002","journal-title":"Cancer Research"},{"key":"10.1016\/j.biocel.2012.06.028_bib0110","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1046\/j.1365-2443.2003.00615.x","article-title":"A possible linkage between AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signalling pathway","volume":"8","author":"Kimura","year":"2003","journal-title":"Genes Cells"},{"key":"10.1016\/j.biocel.2012.06.028_bib0115","doi-asserted-by":"crossref","first-page":"59","DOI":"10.4161\/auto.1.1.1536","article-title":"Autophagy and p70S6 kinase","volume":"1","author":"Klionsky","year":"2005","journal-title":"Autophagy"},{"key":"10.1016\/j.biocel.2012.06.028_bib0120","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1038\/nrc1692","article-title":"The role of autophagy in cancer development and response to therapy","volume":"5","author":"Kondo","year":"2005","journal-title":"Nature Reviews Cancer"},{"key":"10.1016\/j.biocel.2012.06.028_bib0125","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1227\/01.NEU.0000311080.43024.0E","article-title":"Targeting the alpha 1 subunit of the sodium pump to combat glioblastoma cells","volume":"62","author":"Lefranc","year":"2008","journal-title":"Neurosurgery"},{"key":"10.1016\/j.biocel.2012.06.028_bib0130","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/S1534-5807(04)00099-1","article-title":"Development by self-digestion: molecular mechanisms and biological functions of autophagy","volume":"6","author":"Levine","year":"2004","journal-title":"Developmental Cell"},{"key":"10.1016\/j.biocel.2012.06.028_bib0135","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1038\/45257","article-title":"Induction of autophagy and inhibition of tumorigenesis by beclin 1","volume":"402","author":"Liang","year":"1999","journal-title":"Nature"},{"key":"10.1016\/j.biocel.2012.06.028_bib0140","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1517\/14728222.11.8.1043","article-title":"Digitoxin as an anticancer agent with selectivity for cancer cells: possible mechanisms involved","volume":"11","author":"Lopez-Lazaro","year":"2007","journal-title":"Expert Opinion on Therapeutic Targets"},{"key":"10.1016\/j.biocel.2012.06.028_bib0145","doi-asserted-by":"crossref","first-page":"1642","DOI":"10.1021\/np050226l","article-title":"Digitoxin inhibits the growth of cancer cell lines at concentrations commonly found in cardiac patients","volume":"68","author":"Lopez-Lazaro","year":"2005","journal-title":"Journal of Natural Products"},{"key":"10.1016\/j.biocel.2012.06.028_bib0150","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1038\/nrm2239","article-title":"Self-eating and self-killing: crosstalk between autophagy and apoptosis","volume":"8","author":"Maiuri","year":"2007","journal-title":"Nature Reviews Molecular Cell Biology"},{"key":"10.1016\/j.biocel.2012.06.028_bib0155","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/S1097-2765(02)00568-3","article-title":"Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase\/akt pathway","volume":"10","author":"Manning","year":"2002","journal-title":"Molecular Cell"},{"key":"10.1016\/j.biocel.2012.06.028_bib0160","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1016\/j.mad.2010.10.003","article-title":"Salidroside protects human fibroblast cells from premature senescence induced by H(2)O(2) partly through modulating oxidative status","volume":"131","author":"Mao","year":"2010","journal-title":"Mechanisms of Ageing and Development"},{"key":"10.1016\/j.biocel.2012.06.028_bib0165","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1593\/neo.05850","article-title":"Cardenolide-induced lysosomal membrane permeabilization demonstrates therapeutic benefits in experimental human non-small cell lung cancers","volume":"8","author":"Mijatovic","year":"2006","journal-title":"Neoplasia"},{"key":"10.1016\/j.biocel.2012.06.028_bib0170","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1002\/path.2172","article-title":"The alpha1 subunit of the sodium pump could represent a novel target to combat non-small cell lung cancers","volume":"212","author":"Mijatovic","year":"2007","journal-title":"Journal of Pathology"},{"key":"10.1016\/j.biocel.2012.06.028_bib0175","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1177\/1534735407309623","article-title":"Autophagic cell death of human pancreatic tumor cells mediated by oleandrin, a lipid-soluble cardiac glycoside","volume":"6","author":"Newman","year":"2007","journal-title":"Integrative Cancer Therapies"},{"key":"10.1016\/j.biocel.2012.06.028_bib0180","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1124\/mi.8.1.8","article-title":"Cardiac glycosides as novel cancer therapeutic agents","volume":"8","author":"Newman","year":"2008","journal-title":"Molecular Interventions"},{"key":"10.1016\/j.biocel.2012.06.028_bib0185","doi-asserted-by":"crossref","first-page":"39090","DOI":"10.1074\/jbc.M006198200","article-title":"Erk1\/2-dependent phosphorylation of Galpha-interacting protein stimulates its GTPase accelerating activity and autophagy in human colon cancer cells","volume":"275","author":"Ogier-Denis","year":"2000","journal-title":"Journal of Biological Chemistry"},{"key":"10.1016\/j.biocel.2012.06.028_bib0190","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1038\/35056522","article-title":"Molecular dissection of autophagy: two ubiquitin-like systems","volume":"2","author":"Ohsumi","year":"2001","journal-title":"Nature Reviews Molecular Cell Biology"},{"key":"10.1016\/j.biocel.2012.06.028_bib0195","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1038\/nrc1412","article-title":"Pathways of apoptotic and non-apoptotic death in tumour cells","volume":"4","author":"Okada","year":"2004","journal-title":"Nature Reviews Cancer"},{"key":"10.1016\/j.biocel.2012.06.028_bib0200","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1006\/mcne.2002.1184","article-title":"Tsc2 null murine neuroepithelial cells are a model for human tuber giant cells, and show activation of an mTOR pathway","volume":"21","author":"Onda","year":"2002","journal-title":"Molecular and Cellular Neuroscience"},{"key":"10.1016\/j.biocel.2012.06.028_bib0205","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1111\/j.1749-6632.2009.05117.x","article-title":"The tuberous sclerosis complex","volume":"1184","author":"Orlova","year":"2010","journal-title":"Annals of the New York Academy of Sciences"},{"key":"10.1016\/j.biocel.2012.06.028_bib0210","first-page":"439","article-title":"A novel response of cancer cells to radiation involves autophagy and formation of acidic vesicles","volume":"61","author":"Paglin","year":"2001","journal-title":"Cancer Research"},{"key":"10.1016\/j.biocel.2012.06.028_bib0215","doi-asserted-by":"crossref","first-page":"16667","DOI":"10.1074\/jbc.M210998200","article-title":"Amino acids interfere with the ERK1\/2-dependent control of macroautophagy by controlling the activation of Raf-1 in human colon cancer HT-29 cells","volume":"278","author":"Pattingre","year":"2003","journal-title":"Journal of Biological Chemistry"},{"key":"10.1016\/j.biocel.2012.06.028_bib0220","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1038\/nrd2682","article-title":"Novel therapeutic applications of cardiac glycosides","volume":"7","author":"Prassas","year":"2008","journal-title":"Nature Reviews Drug Discovery"},{"key":"10.1016\/j.biocel.2012.06.028_bib0225","doi-asserted-by":"crossref","first-page":"E715","DOI":"10.1152\/ajpendo.2000.279.4.E715","article-title":"4E-BP1 and S6K1: translational integration sites for nutritional and hormonal information in muscle","volume":"279","author":"Shah","year":"2000","journal-title":"American Journal of Physiology\u2014Endocrinology and Metabolism"},{"key":"10.1016\/j.biocel.2012.06.028_bib0230","doi-asserted-by":"crossref","first-page":"380","DOI":"10.4161\/auto.5.3.7658","article-title":"Prognostic significance of Beclin 1-dependent apoptotic activity in hepatocellular carcinoma","volume":"5","author":"Shi","year":"2009","journal-title":"Autophagy"},{"key":"10.1016\/j.biocel.2012.06.028_bib0235","doi-asserted-by":"crossref","first-page":"635","DOI":"10.4161\/auto.4916","article-title":"Roles of the Akt\/mTOR\/p70S6K and ERK1\/2 signaling pathways in curcumin-induced autophagy","volume":"3","author":"Shinojima","year":"2007","journal-title":"Autophagy"},{"key":"10.1016\/j.biocel.2012.06.028_bib0240","doi-asserted-by":"crossref","first-page":"14921","DOI":"10.1074\/jbc.M808355200","article-title":"Changes in sodium pump expression dictate the effects of ouabain on cell growth","volume":"284","author":"Tian","year":"2009","journal-title":"Journal of Biological Chemistry"},{"key":"10.1016\/j.biocel.2012.06.028_bib0245","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1016\/j.biocel.2011.05.010","article-title":"Core signaling pathways of survival\/death in autophagy-related cancer networks","volume":"43","author":"Wang","year":"2011","journal-title":"International Journal of Biochemistry & Cell Biology"},{"key":"10.1016\/j.biocel.2012.06.028_bib0250","doi-asserted-by":"crossref","first-page":"6556","DOI":"10.1158\/0008-5472.CAN-09-0891","article-title":"Cardiac glycosides inhibit p53 synthesis by a mechanism relieved by Src or MAPK inhibition","volume":"69","author":"Wang","year":"2009","journal-title":"Cancer Research"},{"key":"10.1016\/j.biocel.2012.06.028_bib0255","doi-asserted-by":"crossref","first-page":"2165","DOI":"10.2741\/1688","article-title":"Na\/K-ATPase, endogenous digitalis like compounds and cancer development\u2014a hypothesis","volume":"10","author":"Weidemann","year":"2005","journal-title":"Frontier in Biosciences"},{"key":"10.1016\/j.biocel.2012.06.028_bib0260","doi-asserted-by":"crossref","first-page":"e9996","DOI":"10.1371\/journal.pone.0009996","article-title":"Simultaneous induction of non-canonical autophagy and apoptosis in cancer cells by ROS-dependent ERK and JNK activation","volume":"5","author":"Wong","year":"2010","journal-title":"PLoS One"},{"key":"10.1016\/j.biocel.2012.06.028_bib0265","doi-asserted-by":"crossref","first-page":"19579","DOI":"10.1073\/pnas.0809763105","article-title":"Digoxin and other cardiac glycosides inhibit HIF-1alpha synthesis and block tumor growth","volume":"105","author":"Zhang","year":"2008","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"}],"container-title":["The International Journal of Biochemistry & Cell Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1357272512002270?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1357272512002270?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T06:51:09Z","timestamp":1761202269000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S1357272512002270"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,11]]},"references-count":53,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2012,11]]}},"alternative-id":["S1357272512002270"],"URL":"https:\/\/doi.org\/10.1016\/j.biocel.2012.06.028","relation":{},"ISSN":["1357-2725"],"issn-type":[{"value":"1357-2725","type":"print"}],"subject":[],"published":{"date-parts":[[2012,11]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Cardiac glycosides induce autophagy in human non-small cell lung cancer cells through regulation of dual signaling pathways","name":"articletitle","label":"Article Title"},{"value":"The International Journal of Biochemistry & Cell Biology","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.biocel.2012.06.028","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"Copyright \u00a9 2012 Elsevier Ltd. All rights reserved.","name":"copyright","label":"Copyright"}]}}