{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T21:06:27Z","timestamp":1790024787537,"version":"4.0.1"},"reference-count":59,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2019,5,20]],"date-time":"2019-05-20T00:00:00Z","timestamp":1558310400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R15CA227946"],"award-info":[{"award-number":["R15CA227946"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"DOI":"10.1371\/journal.pone.0217038","type":"journal-article","created":{"date-parts":[[2019,5,20]],"date-time":"2019-05-20T13:32:31Z","timestamp":1558359151000},"page":"e0217038","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":17,"title":["Carvedilol inhibits EGF-mediated JB6 P+ colony formation through a mechanism independent of adrenoceptors"],"prefix":"10.1371","volume":"14","author":[{"given":"Kristan H.","family":"Cleveland","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sherry","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andy","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6561-3295","authenticated-orcid":true,"given":"Kevin M.","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Si","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3948-7456","authenticated-orcid":true,"given":"Bradley T.","family":"Andresen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2019,5,20]]},"reference":[{"issue":"1","key":"ref1","doi-asserted-by":"crossref","first-page":"45","DOI":"10.4065\/77.1.45","article-title":"Autonomic tone as a cardiovascular risk factor: the dangers of chronic fight or flight","volume":"77","author":"BM Curtis","year":"2002","journal-title":"Mayo Clin Proc"},{"issue":"11","key":"ref2","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1007\/s00262-014-1617-9","article-title":"A nervous tumor microenvironment: the impact of adrenergic stress on cancer cells, immunosuppression, and immunotherapeutic response","volume":"63","author":"JW Eng","year":"2014","journal-title":"Cancer Immunol Immunother"},{"issue":"18","key":"ref3","doi-asserted-by":"crossref","first-page":"7042","DOI":"10.1158\/0008-5472.CAN-10-0522","article-title":"The sympathetic nervous system induces a metastatic switch in primary breast cancer","volume":"70","author":"EK Sloan","year":"2010","journal-title":"Cancer Res"},{"issue":"2","key":"ref4","first-page":"369","article-title":"Stress hormone-mediated invasion of ovarian cancer cells","volume":"12","author":"AK Sood","year":"2006","journal-title":"ClinCancer Res"},{"issue":"1","key":"ref5","first-page":"153","article-title":"Beta-adrenergic and arachidonic acid-mediated growth regulation of human breast cancer cell lines","volume":"21","author":"Y Cakir","year":"2002","journal-title":"IntJOncol"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1038\/ncomms2413","article-title":"Src activation by beta-adrenoreceptors is a key switch for tumour metastasis","volume":"4","author":"GN Armaiz-Pena","year":"2013","journal-title":"Nat Commun"},{"issue":"7600","key":"ref7","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1136\/bmj.39185.440382.47","article-title":"Beta blockers in hypertension and cardiovascular disease","volume":"334","author":"HT Ong","year":"2007","journal-title":"BMJ"},{"issue":"5","key":"ref8","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1517\/13543784.2016.1164141","article-title":"Immunological and pleiotropic effects of individual beta-blockers and their relevance in cancer therapies","volume":"25","author":"JF Chung","year":"2016","journal-title":"Expert opinion on investigational drugs"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.ijcard.2015.02.015","article-title":"Carvedilol use is associated with reduced cancer risk: A nationwide population-based cohort study","volume":"184","author":"CS Lin","year":"2015","journal-title":"International journal of cardiology"},{"issue":"5","key":"ref10","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1158\/1078-0432.CCR-11-0641","article-title":"Molecular pathways: beta-adrenergic signaling in cancer","volume":"18","author":"SW Cole","year":"2012","journal-title":"Clin Cancer Res"},{"issue":"19","key":"ref11","doi-asserted-by":"crossref","first-page":"3380","DOI":"10.1002\/cncr.29394","article-title":"Are beta-blockers on the therapeutic horizon for ovarian cancer treatment?","volume":"121","author":"KP Bunch","year":"2015","journal-title":"Cancer"},{"issue":"2","key":"ref12","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.jclinane.2013.10.004","article-title":"Perioperative beta-blocker use and survival in lung cancer patients","volume":"26","author":"JP Cata","year":"2014","journal-title":"J Clin Anesth"},{"issue":"1","key":"ref13","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1158\/1940-6207.CAPR-14-0193","article-title":"Prevention of skin carcinogenesis by the beta-blocker carvedilol","volume":"8","author":"A Chang","year":"2015","journal-title":"Cancer prevention research"},{"key":"ref14","article-title":"Topically Applied Carvedilol Attenuates Solar Ultraviolet Radiation Induced Skin Carcinogenesis","author":"KM Huang","year":"2017","journal-title":"Cancer prevention research"},{"issue":"2","key":"ref15","first-page":"92","article-title":"A pharmacological primer of biased agonism","volume":"11","author":"BT Andresen","year":"2011","journal-title":"EndocrMetab ImmuneDisordDrug Targets"},{"issue":"42","key":"ref16","doi-asserted-by":"crossref","first-page":"16657","DOI":"10.1073\/pnas.0707936104","article-title":"A unique mechanism of beta-blocker action: carvedilol stimulates beta-arrestin signaling","volume":"104","author":"JW Wisler","year":"2007","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1146\/annurev.pharmtox.010909.105800","article-title":"Molecular mechanism of beta-arrestin-biased agonism at seven-transmembrane receptors","volume":"52","author":"E Reiter","year":"2012","journal-title":"Annu Rev Pharmacol Toxicol"},{"issue":"1","key":"ref18","first-page":"92","article-title":"Carvedilol, a new vasodilator and beta adrenoceptor antagonist, is an antioxidant and free radical scavenger","volume":"263","author":"TL Yue","year":"1992","journal-title":"J Pharmacol Exp Ther"},{"key":"ref19","article-title":"Phosphoproteome profiling provides insight into the mechanism of action for carvedilol-mediated cancer prevention","author":"KH Cleveland","year":"2018","journal-title":"Molecular carcinogenesis"},{"key":"ref20","first-page":"67","article-title":"Food Factors for Cancer Prevention","author":"JL Cmarik","year":"1997"},{"issue":"5","key":"ref21","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1007\/BF00376622","article-title":"High density of beta 2-adrenoceptors in a human keratinocyte cell line with complete epidermal differentiation capacity (HaCaT)","volume":"283","author":"V Steinkraus","year":"1991","journal-title":"Arch Dermatol Res"},{"issue":"24","key":"ref22","doi-asserted-by":"crossref","first-page":"16701","DOI":"10.1074\/jbc.274.24.16701","article-title":"Cardiovascular and metabolic alterations in mice lacking both beta1- and beta2-adrenergic receptors","volume":"274","author":"DK Rohrer","year":"1999","journal-title":"J Biol Chem"},{"issue":"7442","key":"ref23","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1038\/nature12000","article-title":"Conformational biosensors reveal GPCR signalling from endosomes","volume":"495","author":"R Irannejad","year":"2013","journal-title":"Nature"},{"issue":"4","key":"ref24","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1016\/j.cardiores.2004.05.014","article-title":"Carvedilol selectively inhibits oscillatory intracellular calcium changes evoked by human alpha1D- and alpha1B-adrenergic receptors","volume":"63","author":"TA Koshimizu","year":"2004","journal-title":"Cardiovascular research"},{"issue":"12","key":"ref25","first-page":"1615","article-title":"An efficient improved synthesis of carvedilol, via 2-(2-methoxyphenoxy)ethyl 4-methylbenzenesulfonate intermediate","volume":"53B","author":"KT Reddy","year":"2014","journal-title":"IJC-B"},{"key":"ref26","article-title":"Anti-cancer activity of carvedilol and its isomers","author":"AC Burman","year":"2003","journal-title":"Google Patents"},{"issue":"3","key":"ref27","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/sj.bjp.0706048","article-title":"The selectivity of beta-adrenoceptor antagonists at the human beta1, beta2 and beta3 adrenoceptors","volume":"144","author":"JG Baker","year":"2005","journal-title":"Br J Pharmacol"},{"issue":"1","key":"ref28","first-page":"162","article-title":"Conformational rearrangements and signaling cascades involved in ligand-biased mitogen-activated protein kinase signaling through the beta1-adrenergic receptor","volume":"74","author":"S Galandrin","year":"2008","journal-title":"MolPharmacol"},{"issue":"20","key":"ref29","doi-asserted-by":"crossref","first-page":"11406","DOI":"10.1073\/pnas.1936664100","article-title":"Beta-arrestin-mediated activation of MAPK by inverse agonists reveals distinct active conformations for G protein-coupled receptors","volume":"100","author":"M Azzi","year":"2003","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"6","key":"ref30","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1111\/j.2042-7158.1978.tb13268.x","article-title":"Interaction of 2-[beta-(4-hydroxyphenyl)ethylaminomethyl]tertralone (BE-2254: 'HEAT') with catecholamine receptors in rat brain membranes","volume":"30","author":"M Williams","year":"1978","journal-title":"J Pharm Pharmacol"},{"issue":"1","key":"ref31","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/0163-7258(92)90051-Z","article-title":"Multistage carcinogenesis in mouse skin","volume":"54","author":"J. DiGiovanni","year":"1992","journal-title":"Pharmacol Ther"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"6426","DOI":"10.1038\/ncomms7426","article-title":"Housing temperature-induced stress drives therapeutic resistance in murine tumour models through beta2-adrenergic receptor activation","volume":"6","author":"JW Eng","year":"2015","journal-title":"Nat Commun"},{"issue":"1","key":"ref33","first-page":"19","article-title":"beta2-adrenergic antagonists suppress pancreatic cancer cell invasion by inhibiting CREB, NFkappaB and AP-1","volume":"10","author":"D Zhang","year":"2010","journal-title":"Cancer BiolTher"},{"issue":"11","key":"ref34","first-page":"2744","article-title":"The norepinephrine-driven metastasis development of PC-3 human prostate cancer cells in BALB\/c nude mice is inhibited by beta-blockers","volume":"118","author":"D Palm","year":"2006","journal-title":"IntJCancer"},{"issue":"18","key":"ref35","doi-asserted-by":"crossref","first-page":"7042","DOI":"10.1158\/0008-5472.CAN-10-0522","article-title":"The sympathetic nervous system induces a metastatic switch in primary breast cancer","volume":"70","author":"EK Sloan","year":"2010","journal-title":"Cancer research"},{"issue":"4","key":"ref36","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1097\/HJH.0b013e3280127948","article-title":"Antioxidant activity of carvedilol in cardiovascular disease","volume":"25","author":"P Dandona","year":"2007","journal-title":"J Hypertens"},{"issue":"2","key":"ref37","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1097\/00005344-200008000-00020","article-title":"A comparison of carvedilol and metoprolol antioxidant activities in vitro","volume":"36","author":"PG Lysko","year":"2000","journal-title":"J Cardiovasc Pharmacol"},{"issue":"2\u20133","key":"ref38","first-page":"209","article-title":"Carvedilol, a new antihypertensive, prevents oxidation of human low density lipoprotein by macrophages and copper","volume":"97","author":"TL Yue","year":"1992","journal-title":"Atherosclerosis"},{"issue":"8","key":"ref39","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1038\/nm.2406","article-title":"Carvedilol and its new analogs suppress arrhythmogenic store overload-induced Ca2+ release","volume":"17","author":"Q Zhou","year":"2011","journal-title":"Nat Med"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1111\/j.1749-6632.2002.tb02918.x","article-title":"Cancer chemopreventive activity of resveratrol","volume":"957","author":"KP IBhat","year":"2002","journal-title":"Ann N Y Acad Sci"},{"issue":"13","key":"ref41","doi-asserted-by":"crossref","first-page":"2475","DOI":"10.1091\/mbc.E14-10-1453","article-title":"Regulation of cell proliferation by ERK and signal-dependent nuclear translocation of ERK is dependent on Tm5NM1-containing actin filaments","volume":"26","author":"G Schevzov","year":"2015","journal-title":"Molecular biology of the cell"},{"issue":"12","key":"ref42","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.4161\/cbt.3.12.1233","article-title":"EGF activates intracellular and intercellular calcium signaling by distinct pathways in tumor cells","volume":"3","author":"JA Bryant","year":"2004","journal-title":"Cancer Biol Ther"},{"issue":"38","key":"ref43","doi-asserted-by":"crossref","first-page":"14555","DOI":"10.1073\/pnas.0804745105","article-title":"Beta-blockers alprenolol and carvedilol stimulate beta-arrestin-mediated EGFR transactivation","volume":"105","author":"IM Kim","year":"2008","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"3","key":"ref44","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1124\/mol.113.088880","article-title":"Quantification of ligand bias for clinically relevant beta2-adrenergic receptor ligands: implications for drug taxonomy","volume":"85","author":"ET van der Westhuizen","year":"2014","journal-title":"Molecular pharmacology"},{"issue":"5","key":"ref45","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1111\/j.1365-2125.1980.tb05849.x","article-title":"Some further evidence for partial agonist activity of labetalol","volume":"9","author":"AJ Riley","year":"1980","journal-title":"Br J Clin Pharmacol"},{"issue":"8","key":"ref46","doi-asserted-by":"crossref","first-page":"e71980","DOI":"10.1371\/journal.pone.0071980","article-title":"The beta-blocker Nebivolol Is a GRK\/beta-arrestin Biased Agonist","volume":"8","author":"CE Erickson","year":"2013","journal-title":"PloS one"},{"issue":"9","key":"ref47","doi-asserted-by":"crossref","first-page":"1683","DOI":"10.1016\/0006-2952(91)90502-V","article-title":"Human beta 1- and beta 2-adrenergic receptor binding and mediated accumulation of cAMP in transfected Chinese hamster ovary cells. Profile of nebivolol and known beta-adrenergic blockers","volume":"42","author":"PJ Pauwels","year":"1991","journal-title":"Biochemical pharmacology"},{"issue":"3","key":"ref48","first-page":"490","article-title":"Inverse agonist activity of beta-adrenergic antagonists","volume":"45","author":"P Chidiac","year":"1994","journal-title":"Molecular pharmacology"},{"issue":"6519","key":"ref49","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1038\/374272a0","article-title":"Physiological effects of inverse agonists in transgenic mice with myocardial overexpression of the beta 2-adrenoceptor","volume":"374","author":"RA Bond","year":"1995","journal-title":"Nature"},{"issue":"1","key":"ref50","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1038\/sj.bjp.0703535","article-title":"Non-competitive antagonism of beta(2)-agonist-mediated cyclic AMP accumulation by ICI 118551 in BC3H1 cells endogenously expressing constitutively active beta(2)-adrenoceptors","volume":"131","author":"HE Hopkinson","year":"2000","journal-title":"Br J Pharmacol"},{"issue":"6","key":"ref51","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1124\/mol.64.6.1357","article-title":"Agonist and inverse agonist actions of beta-blockers at the human beta 2-adrenoceptor provide evidence for agonist-directed signaling","volume":"64","author":"JG Baker","year":"2003","journal-title":"Molecular pharmacology"},{"issue":"3","key":"ref52","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1161\/01.CIR.0000080325.94345.8B","article-title":"Partial agonist activity of bucindolol is dependent on the activation state of the human beta1-adrenergic receptor","volume":"108","author":"C Maack","year":"2003","journal-title":"Circulation"},{"issue":"3","key":"ref53","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1038\/sj.bjp.0704855","article-title":"Pharmacological characterization of CGP 12177 at the human beta(2)-adrenoceptor","volume":"137","author":"JG Baker","year":"2002","journal-title":"Br J Pharmacol"},{"issue":"33","key":"ref54","doi-asserted-by":"crossref","first-page":"11443","DOI":"10.1021\/ja105108q","article-title":"Conserved binding mode of human beta2 adrenergic receptor inverse agonists and antagonist revealed by X-ray crystallography","volume":"132","author":"D Wacker","year":"2010","journal-title":"J Am Chem Soc"},{"issue":"2","key":"ref55","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1161\/01.RES.49.2.326","article-title":"Characterization of [3H](+\/-)carazolol binding to beta-adrenergic receptors. Application to study of beta-adrenergic receptor subtypes in canine ventricular myocardium and lung","volume":"49","author":"AS Manalan","year":"1981","journal-title":"Circ Res"},{"issue":"5","key":"ref56","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1111\/j.1365-2125.1978.tb01647.x","article-title":"A comparison of four beta-adrenoceptor antagonists in patients with asthma","volume":"5","author":"MK Benson","year":"1978","journal-title":"Br J Clin Pharmacol"},{"issue":"3","key":"ref57","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1016\/j.coph.2010.03.002","article-title":"beta-Adrenoceptor inverse agonists in asthma","volume":"10","author":"BF Dickey","year":"2010","journal-title":"Curr Opin Pharmacol"},{"issue":"4","key":"ref58","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1002\/jmr.949","article-title":"Analysis of full and partial agonists binding to beta2-adrenergic receptor suggests a role of transmembrane helix V in agonist-specific conformational changes","volume":"22","author":"V Katritch","year":"2009","journal-title":"Journal of molecular recognition: JMR"},{"issue":"3","key":"ref59","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/0014-2999(82)90106-6","article-title":"Specificity of the beta 2-adrenergic receptor stimulating cyclic AMP accumulation in the intermediate lobe of rat pituitary gland","volume":"81","author":"H Meunier","year":"1982","journal-title":"European journal of pharmacology"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.pone.0217038","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,5,8]],"date-time":"2020-05-08T18:29:57Z","timestamp":1588962597000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0217038"}},"subtitle":[],"editor":[{"given":"Aamir","family":"Ahmad","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2019,5,20]]},"references-count":59,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2019,5,20]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0217038","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,5,20]]}}}