Abstract
Hepatocellular carcinoma (HCC) has been recognized worldwide as one of the major causes of cancer death. The medicinal fungus Antrodia cinnamomea (A. cinnamomea) has been served as a functional food for liver protection. The aim of the present study was to investigate the potential activity of A. cinnamomea extracts as a safe booster for the anticancer activity of sorafenib, a multi-kinase inhibitor approved for the treatment of HCC. The biologically active triterpenoids in the ethanolic extracts of A. cinnamomea (EAC) were initially identified by HPLC/LC/MS then the different extracts and sorafenib were assessed in vitro and in vivo. EAC could effectively sensitize HCC cells to low doses of sorafenib, which was perceived via the ability of the combination to repress cell viability and to induce cell cycle arrest and apoptosis in HCC cells. The ability of EAC to enhance sorafenib activity was mediated through targeting mitogen-activated protein (MAP) kinases, modulating cyclin proteins expression and inhibiting cancer cell invasion. Moreover, the proposed combination significantly suppressed ectopic tumor growth in mice with high safety margins compared to single-agent treatment. Thus, this study highlights the advantage of combining EAC with sorafenib as a potential adjuvant therapeutic strategy against HCC.
Highlights
Hepatocellular carcinoma (HCC) affects approximately one million people worldwide annually[1,2,3]
To identify the metabolite profile of the samples obtained from different growth substrates, the HPLC fingerprint of the wild fruiting body ethanolic extract of A. cinnamomea (EACF) was used as a standard (Fig. 1B)
Our result indicated that extracts of A. cinnamomea (EAC) extract contains those important triterpenoids as detected by UV, total ion chromatogram (TIC) and LC/MS/MS analysis (Supplementary Material Part 1)
Summary
Hepatocellular carcinoma (HCC) affects approximately one million people worldwide annually[1,2,3]. Sorafenib targets mainly RAF signaling in addition to VEGF (vascular endothelial growth factor), PDGF (platelet derived growth factor), and c-Kit, which results in significant antiproliferative and antiangiogenic activity in HCC12–14. To expand the efficacy of sorafenib, many studies have demonstrated a successful therapeutic combination of sorafenib and other agents targeting parallel signaling pathways. Anti-inflammatory and hepatoprotective properties of the active components of A. cinnamomea extracts have been reported previously[23,24,25]. The introduction of A. cinnamomea extract as an adjuvant medication to sorafenib in HCC therapeutic protocols has not been explored previously. Our aim was to explore the cytotoxic activity of sorafenib and A. cinnamomea extract against human liver cancer cells with a special emphasis on the possible synergistic mechanisms via ERK signaling pathways, both in vitro and in vivo. The outcome of the present study may provide a basis to develop a novel formula of EAC extract to be used in HCC therapeutic protocols
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