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Molecules 2017, 22(7), 1175; doi:10.3390/molecules22071175

Evodiamine Exerts an Anti-Hepatocellular Carcinoma Activity through a WWOX-Dependent Pathway

1,2,†
,
3,4,†
,
3,5,6
,
1,7
,
4,* and 1,6,*
1
Graduate Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
2
Department of Urology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
3
Research Center of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
4
Department of Family Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
5
Department of Otolaryngology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
6
Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
7
Division of Endocrinology and Metabolism, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
Che-Yuan Hu and Hung-Tsung Wu contribute equally to this work.
*
Authors to whom correspondence should be addressed.
Received: 2 June 2017 / Revised: 28 June 2017 / Accepted: 4 July 2017 / Published: 14 July 2017
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Abstract

Evodiamine is one of the main components isolated from Evodia rutaecarpa, and it has been reported to exert inhibitory effects on cancers by anti-proliferative and apoptosis-inducing activities. Although the anti-cancer activity of evodiamine has been identified, the precise mechanisms of this action remain obscure. While previous studies indicated that evodiamine exerts anti-tumor effects through inhibiting β-catenin activity, and WW domain-containing oxidoreductase (WWOX) regulates β-catenin accumulation in cytoplasm, the effects of evodiamine on the expression of WWOX are still unknown. In this study, we provide evidence that evodiamine dose- and time-dependently inhibits both Mus musculus and Homo sapiens hepatocellular carcinoma (HCC) cells, as well as Hepa1-6 and HepG2 cell proliferation. We further tested the therapeutic effects of evodiamine in Hepa1-6 hepatoma-bearing mice, and we found that treatment of evodiamine by oral gavage significantly decreased the tumor size of the mice. Moreover, the expressions of WWOX were dose-dependently increased in HCC cell lines as well as in Hepa1-6 hepatoma-bearing mice after the treatment with evodiamine. Knockdown of WWOX in HepG2 and Hepa1-6 cells diminished the effects of evodiamine on the inhibitory effect of cancer cell growth, indicating that evodiamine induced anti-cancer activity through a WWOX-dependent pathway. As such, evodiamine activated WWOX to exert an anti-HCC activity, and might be a potential therapeutic or preventive candidate for HCC treatment. View Full-Text
Keywords: Evodia rutaecarpa; evodiamine; hepatocellular carcinoma; herbal medicine; WW domain-containing oxidoreductase Evodia rutaecarpa; evodiamine; hepatocellular carcinoma; herbal medicine; WW domain-containing oxidoreductase
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MDPI and ACS Style

Hu, C.-Y.; Wu, H.-T.; Su, Y.-C.; Lin, C.-H.; Chang, C.-J.; Wu, C.-L. Evodiamine Exerts an Anti-Hepatocellular Carcinoma Activity through a WWOX-Dependent Pathway. Molecules 2017, 22, 1175.

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