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

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.

Antiproliferative Effects of Alkaloid Evodiamine and Its Derivatives

“…And the inhibition of WWOX reversed the cytotoxic effect of evodiamine. As such, the anti-hepatocellular carcinoma activity of evodiamine was linked with the activation of WWOX [ 46 ]. Activator protein 1 (AP-1) is required for tumor promotion [ 47 ].…”

Evodiamine Inhibits Lipopolysaccharide (LPS)-Induced Inflammation in BV-2 Cells via Regulating AKT/Nrf2-HO-1/NF-κB Signaling Axis

“…Evodiamine (EV) is a natural alkaloid and a primary biologically active ingredient of Evodia rutaecarpa, a medicinal plant used in traditional Chinese medicine (Hu et al 2017). Pharmacological studies have shown that EV binds to a variety of proteins, and so it can be used as a multitarget compound for tumors, obesity, pain, inflammation, cardiovascular disease, and Alzheimer's disease (Cai et al 2014;Wang et al 2013;Wu et al 2013;Yu et al 2013).…”

Evodiamine Mitigates Cellular Growth and Promotes Apoptosis by Targeting the c-Met Pathway in Prostate Cancer Cells

“…A number of drugs isolated from nature have shown potential against different cancers including prostate [20][21][22][23][24][25][26][27][28][29][30][31][32]. Evodiamine (EVO) is an indoloquinazoline alkaloid reported to have various pharmacological effects including anti-proliferation [33][34][35], and anti-tumor properties [36,37], and can cause both cell cycle arrest [38,39] and apoptosis [40,41] in vitro and in vivo. According to previous studies, EVO can effectively block PI3K/protein kinase B (Akt), MAPK, and nuclear factor kappa B (NF-κB) signaling pathways and enhance apoptosis [33,[42][43][44].…”