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Improved Survival in Hepatocellular Carcinoma Patients with Cardiac Arrhythmia by Amiodarone Treatment through Autophagy

1
Department of Chinese Medicine, China Medical University Hospital, Taichung 404, Taiwan
2
School of Chinese Medicine, China Medical University, Taichung 404, Taiwan
3
Cancer Research Center for Traditional Chinese Medicine, Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan
4
Chinese Medicine Research Center, China Medical University, Taichung 404, Taiwan
5
Research Center for Chinese Herbal Medicine, China Medical University, Taichung 404, Taiwan
6
An-Nan Hospital, China Medical University, Tainan 404, Taiwan
7
Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan
8
Management Office for Health Data, China Medical University Hospital, Taichung 404, Taiwan
9
Research Center for Traditional Chinese Medicine, Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(16), 3978; https://doi.org/10.3390/ijms20163978
Received: 14 July 2019 / Accepted: 13 August 2019 / Published: 15 August 2019
(This article belongs to the Section Molecular Oncology)
PDF [2165 KB, uploaded 15 August 2019]
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Abstract

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.
Keywords: amiodarone; autophagy; hepatocellular carcinoma; National Health Insurance Research Database amiodarone; autophagy; hepatocellular carcinoma; National Health Insurance Research Database
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Huang, S.-T.; Hsu, W.-F.; Huang, H.-S.; Yen, J.-H.; Lin, M.-C.; Peng, C.-Y.; Yen, H.-R. Improved Survival in Hepatocellular Carcinoma Patients with Cardiac Arrhythmia by Amiodarone Treatment through Autophagy. Int. J. Mol. Sci. 2019, 20, 3978.

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