{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,8]],"date-time":"2026-02-08T13:15:25Z","timestamp":1770556525898,"version":"3.49.0"},"reference-count":41,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2019,8,15]],"date-time":"2019-08-15T00:00:00Z","timestamp":1565827200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Health and welfare surcharge of tobacco products, China Medical University Hospital Cancer Research Center of Excellence","award":["MOHW108-TDU-B-212-12402"],"award-info":[{"award-number":["MOHW108-TDU-B-212-12402"]}]},{"DOI":"10.13039\/501100004391","name":"China Medical University Hospital","doi-asserted-by":"publisher","award":["DMR-108-007, DMR-108-009, DMR-108-044, DMR-107-164 and CRS-106-001"],"award-info":[{"award-number":["DMR-108-007, DMR-108-009, DMR-108-044, DMR-107-164 and CRS-106-001"]}],"id":[{"id":"10.13039\/501100004391","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Chinese Medicine Research Center, China Medical University under the Higher Education Sprout Project, Ministry of Education","award":["CMRC-CHM-1"],"award-info":[{"award-number":["CMRC-CHM-1"]}]},{"name":"Ministry of Health and Welfare","award":["MOHW107-TDU-B-212-123004"],"award-info":[{"award-number":["MOHW107-TDU-B-212-123004"]}]},{"name":"China Medical University Hospital, Academia Sinica Stroke Biosignature Project","award":["BM10701010021"],"award-info":[{"award-number":["BM10701010021"]}]},{"name":"MOST Clinical Trial Consortium for Stroke","award":["MOST 107-2321-B-039 -004-"],"award-info":[{"award-number":["MOST 107-2321-B-039 -004-"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hepatocellular carcinoma (HCC) is a primary malignancy of the liver. In basic studies, the regulation of autophagy has offered promising results for HCC treatment. This study aimed to address the question of whether amiodarone can improve survival rates in HCC patients associated with autophagy. Using datasets from the National Health Insurance Research Database, we enrolled patients over 18 years of age that had been diagnosed with HCC between January 1997 and December 2010. Amiodarone and non-amiodarone users were matched at a 1:1 frequency, according to all variables. Additionally, HepG2 cells treated with amiodarone were evaluated by cell viability and autophagic change. Autophagic signaling was examined by immunoblotting and tissue array immunohistochemistry. Of the 10,946 patients diagnosed with HCC, each cohort included 221 patients after 1:1 propensity score matching. The median survival was 36.70 months for the amiodarone users, and 24.48 months for the non-amiodarone users. After adjusting for age, gender, comorbidities and treatment, amiodarone users had a significantly lower risk of mortality. Amiodarone users also demonstrated an improved 3-year survival rate. Furthermore, amiodarone treatment-induced autophagy in HepG2 cells was demonstrated by autophagosome formation associated with increasing LC3B-II, P62, and Beclin-1 expression. Autophagic flux also increased following amiodarone treatment with bafilomycin A1. SiRNA of LC3B knocked down endogenous LC3B formation and restored HepG2 cell viability. This study provides epidemiologic evidence that amiodarone via autophagic degradation machinery may offer survival benefits for HCC patients with a history of arrhythmia. Further randomized, blinded, and placebo-controlled trials are warranted for patients with HCC.<\/jats:p>","DOI":"10.3390\/ijms20163978","type":"journal-article","created":{"date-parts":[[2019,8,15]],"date-time":"2019-08-15T11:11:00Z","timestamp":1565867460000},"page":"3978","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Improved Survival in Hepatocellular Carcinoma Patients with Cardiac Arrhythmia by Amiodarone Treatment through Autophagy"],"prefix":"10.3390","volume":"20","author":[{"given":"Sheng-Teng","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Chinese Medicine, China Medical University Hospital, Taichung 404, Taiwan"},{"name":"School of Chinese Medicine, China Medical University, Taichung 404 Taiwan"},{"name":"Cancer Research Center for Traditional Chinese Medicine, Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan"},{"name":"Chinese Medicine Research Center, China Medical University, Taichung 404, Taiwan"},{"name":"Research Center for Chinese Herbal Medicine, China Medical University, Taichung 404, Taiwan"},{"name":"An-Nan Hospital, China Medical University, Tainan 404, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0738-417X","authenticated-orcid":false,"given":"Wei-Fan","family":"Hsu","sequence":"additional","affiliation":[{"name":"Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hung-Sen","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Chinese Medicine, China Medical University Hospital, Taichung 404, Taiwan"},{"name":"School of Chinese Medicine, China Medical University, Taichung 404 Taiwan"},{"name":"Cancer Research Center for Traditional Chinese Medicine, Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jia-Hau","family":"Yen","sequence":"additional","affiliation":[{"name":"Department of Chinese Medicine, China Medical University Hospital, Taichung 404, Taiwan"},{"name":"School of Chinese Medicine, China Medical University, Taichung 404 Taiwan"},{"name":"Cancer Research Center for Traditional Chinese Medicine, Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mei-Chen","family":"Lin","sequence":"additional","affiliation":[{"name":"Management Office for Health Data, China Medical University Hospital, Taichung 404, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheng-Yuan","family":"Peng","sequence":"additional","affiliation":[{"name":"Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0131-1658","authenticated-orcid":false,"given":"Hung-Rong","family":"Yen","sequence":"additional","affiliation":[{"name":"Department of Chinese Medicine, China Medical University Hospital, Taichung 404, Taiwan"},{"name":"School of Chinese Medicine, China Medical University, Taichung 404 Taiwan"},{"name":"Chinese Medicine Research Center, China Medical University, Taichung 404, Taiwan"},{"name":"Research Center for Chinese Herbal Medicine, China Medical University, Taichung 404, Taiwan"},{"name":"Research Center for Traditional Chinese Medicine, Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,8,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2095","DOI":"10.1016\/S0140-6736(12)61728-0","article-title":"Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: A systematic analysis for the Global Burden of Disease Study 2010","volume":"380","author":"Lozano","year":"2012","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1136\/gutjnl-2013-306627","article-title":"Hepatocellular carcinoma: Clinical frontiers and perspectives","volume":"63","author":"Bruix","year":"2014","journal-title":"Gut"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1056\/NEJMra1001683","article-title":"Hepatocellular carcinoma","volume":"365","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1002\/bjs.7669","article-title":"Systematic review and meta-analysis of survival and disease recurrence after radiofrequency ablation for hepatocellular carcinoma","volume":"98","author":"Tiong","year":"2011","journal-title":"Br. J. Surg."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1053\/jhep.2003.50047","article-title":"Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival","volume":"37","author":"Llovet","year":"2003","journal-title":"Hepatology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1053\/j.gastro.2009.09.006","article-title":"Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: A comprehensive report of long-term outcomes","volume":"138","author":"Salem","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1056\/NEJMoa0708857","article-title":"Sorafenib in advanced hepatocellular carcinoma","volume":"359","author":"Llovet","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_8","first-page":"249","article-title":"2010 guideline for the management of hepatocellular carcinoma recommended by the American Association for the Study of Liver Diseases","volume":"19","author":"He","year":"2011","journal-title":"Chin. J. Hepatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/j.semcdb.2012.01.005","article-title":"Autophagy and cancer cell metabolism","volume":"23","author":"Lozy","year":"2012","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1002\/hep.26659","article-title":"Autophagy suppresses tumorigenesis of hepatitis B virus-associated hepatocellular carcinoma through degradation of microRNA-224","volume":"59","author":"Lan","year":"2014","journal-title":"Hepatology"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Lin, C.W., Chen, Y.S., Lin, C.C., Chen, Y.J., Lo, G.H., Lee, P.H., Kuo, P.L., Dai, C.Y., Huang, J.F., and Chung, W.L. (2015). Amiodarone as an autophagy promoter reduces liver injury and enhances liver regeneration and survival in mice after partial hepatectomy. Sci. Rep., 5.","DOI":"10.1038\/srep15807"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5788","DOI":"10.18632\/oncotarget.6810","article-title":"Induction of autophagy promotes the growth of early preneoplastic rat liver nodules","volume":"7","author":"Kowalik","year":"2016","journal-title":"Oncotarget"},{"key":"ref_13","unstructured":"NHIA (2015). National Health Insurance Annual Report 2015\u20132016, National Health Insurance Administration, Ministry of Health and Welfare."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1699","DOI":"10.1002\/cncr.27881","article-title":"Amiodarone and the risk of cancer: A nationwide population-based study","volume":"119","author":"Su","year":"2013","journal-title":"Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1016\/j.ctim.2014.04.002","article-title":"A nationwide population-based study of traditional Chinese medicine usage in children in Taiwan","volume":"22","author":"Huang","year":"2014","journal-title":"Complement. Ther. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1016\/j.hrthm.2007.07.020","article-title":"A practical guide for clinicians who treat patients with amiodarone: 2007","volume":"4","author":"Goldschlager","year":"2007","journal-title":"Heart Rhythm."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1016\/j.jhep.2014.06.019","article-title":"Systemic therapy in HCC: Lessons from brivanib","volume":"61","author":"Bolos","year":"2014","journal-title":"J. Hepatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3389","DOI":"10.1007\/s10620-013-2872-x","article-title":"Combination trans arterial chemoembolization (TACE) plus sorafenib for the management of unresectable hepatocellular carcinoma: A systematic review of the literature","volume":"58","author":"Elsayed","year":"2013","journal-title":"Dig. Dis. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1148\/radiol.14131640","article-title":"Hepatocellular carcinoma: Concomitant sorafenib promotes necrosis after radiofrequency ablation\u2014Propensity score matching analysis","volume":"272","author":"Fukuda","year":"2014","journal-title":"Radiology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1136\/gutjnl-2014-307990","article-title":"Current concepts of immune based treatments for patients with HCC: From basic science to novel treatment approaches","volume":"64","author":"Greten","year":"2015","journal-title":"Gut"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1002\/hep.23676","article-title":"Drug therapy: Sorafenib","volume":"51","author":"Finn","year":"2010","journal-title":"Hepatology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.jcma.2013.11.004","article-title":"Atrial fibrillation influences survival in patients with hepatocellular carcinoma: Experience from a single center in Taiwan","volume":"77","author":"Yang","year":"2014","journal-title":"J. Chin. Med. Assoc."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1687","DOI":"10.4161\/auto.29959","article-title":"Autophagy-preferential degradation of MIR224 participates in hepatocellular carcinoma tumorigenesis","volume":"10","author":"Lan","year":"2014","journal-title":"Autophagy"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Zhou, T., Ye, L., Bai, Y., Sun, A., Cox, B., Liu, D., Li, Y., Liotta, D., Snyder, J.P., and Fu, H. (2014). Autophagy and apoptosis in hepatocellular carcinoma induced by EF25-(GSH)2: A novel curcumin analog. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0107876"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"13390","DOI":"10.18632\/oncotarget.24385","article-title":"Amiodarone promotes cancer cell death through elevated truncated SRSF3 and downregulation of miR-224","volume":"9","author":"Chang","year":"2018","journal-title":"Oncotarget"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1080\/15548627.2019.1569918","article-title":"Degradative autophagy selectively regulates CCND1 (cyclin D1) and MIR224, two oncogenic factors involved in hepatocellular carcinoma tumorigenesis","volume":"15","author":"Wu","year":"2019","journal-title":"Autophagy"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1172\/JCI73941","article-title":"The role for autophagy in cancer","volume":"125","author":"White","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.bcp.2015.03.017","article-title":"A role for the autophagy regulator Transcription Factor EB in amiodarone-induced phospholipidosis","volume":"95","author":"Buratta","year":"2015","journal-title":"Biochem. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Arrigo, M., Bettex, D., and Rudiger, A. (2014). Management of atrial fibrillation in critically ill patients. Crit. Care Res. Pract., 2014.","DOI":"10.1155\/2014\/840615"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.hrtlng.2013.05.004","article-title":"Amiodarone-induced pulmonary toxicity: Case study with syndrome analysis","volume":"42","author":"Yehle","year":"2013","journal-title":"Heart Lung"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1097\/SMJ.0b013e3181e90500","article-title":"Amiodarone and thyroid dysfunction","volume":"103","author":"Padmanabhan","year":"2010","journal-title":"South Med. J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.amjmed.2011.09.020","article-title":"Amiodarone-associated optic neuropathy: A critical review","volume":"125","author":"Passman","year":"2012","journal-title":"Am. J. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1016\/j.jhep.2011.11.020","article-title":"Alpha-fetoprotein response correlates with EASL response and survival in solitary hepatocellular carcinoma treated with transarterial therapies: A subgroup analysis","volume":"56","author":"Memon","year":"2012","journal-title":"J. Hepatol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.1016\/j.jhep.2015.07.013","article-title":"Prognostic impact of surgery and radiofrequency ablation on single nodular HCC 5 cm: Cohort study based on serum HCC markers","volume":"63","author":"Ueno","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1016\/S1470-2045(12)70271-1","article-title":"Biomarkers for early diagnosis of hepatocellular carcinoma","volume":"13","author":"Forner","year":"2012","journal-title":"Lancet Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"S115","DOI":"10.1002\/lt.20034","article-title":"The Barcelona approach: Diagnosis, staging, and treatment of hepatocellular carcinoma","volume":"10","author":"Llovet","year":"2004","journal-title":"Liver Transplant."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1016\/j.jhep.2011.08.017","article-title":"Chemoembolization for intermediate HCC: Is there proof of survival benefit?","volume":"56","author":"Forner","year":"2012","journal-title":"J. Hepatol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Lee, S.H., Kwak, S.C., Kim, D.K., Park, S.W., Kim, H.S., Kim, Y.S., Lee, D., Lee, J.W., Lee, C.G., and Lee, H.K. (2016). Effects of Huang Bai (Phellodendri Cortex) and Three Other Herbs on GnRH and GH Levels in GT1-7 and GH3 Cells. Evid. Based. Complement. Altern. Med., 2016.","DOI":"10.1155\/2016\/9389028"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1016\/j.jhep.2015.07.006","article-title":"Statin use and the risk of cirrhosis development in patients with hepatitis C virus infection","volume":"63","author":"Yang","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1016\/S1470-2045(15)00060-1","article-title":"Risk of leukaemia in children infected with enterovirus: A nationwide, retrospective, population-based, Taiwanese-registry, cohort study","volume":"16","author":"Lin","year":"2015","journal-title":"Lancet Oncol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1906","DOI":"10.1001\/2012.jama.11975","article-title":"Association between nucleoside analogues and risk of hepatitis B virus-related hepatocellular carcinoma recurrence following liver resection","volume":"308","author":"Wu","year":"2012","journal-title":"JAMA"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/16\/3978\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:11:26Z","timestamp":1760188286000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/16\/3978"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,8,15]]},"references-count":41,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2019,8]]}},"alternative-id":["ijms20163978"],"URL":"https:\/\/doi.org\/10.3390\/ijms20163978","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,8,15]]}}}