Abstract
Mistletoe (Viscum album) is a type of parasitic plant reported to have anticancer activity including in hepatocellular carcinoma (HCC). However, the mechanism of mistletoe’s anticancer activity, and its effectiveness in treating HCC are not fully understood. We report here that mistletoe extracts, including Fraxini (grown on ash trees) and Iscador Q and M (grown on oak and maple trees), exert strong antiproliferative activity in Hep3B cells, with median inhibitory concentrations (IC50) of 0.5 µg/mL, 7.49 µg/mL, and 7.51 µg/mL, respectively. Results of Reversed Phase Proteomic Array analysis (RPPA) suggests that Fraxini substantially down-regulates c-Myc expression in Hep3B cells. Fraxini-induced growth inhibition (at a concentration of 1.25 μg/ml) was less pronounced in c-Myc knockdown Hep3B cells than in control cells. Furthermore, in the Hep3B xenograft model, Fraxini-treated (8 mg/kg body weight) mice had significantly smaller tumors (34.6 ± 11.9 mm3) than control mice (161.6 ± 79.4 mm3, p < 0.036). Similarly, c-Myc protein expression was reduced in Fraxini treated Hep3B cell xenografts compared to that of control mice. The reduction of c-Myc protein levels in vitro Hep3B cells appears to be mediated by the ubiquitin-proteasome system. Our results suggest the importance of c-Myc in Fraxini’s antiproliferative activity, which warrants further investigation.
Highlights
The global incidence of hepatocellular carcinoma (HCC) has steadily risen in the last two decades[1,2,3,4,5]
To identify the sensitivity of HCC cells to Mistletoe extract (ME), we first examined the effects of several MEs on the Hep3B cell line
We demonstrated that MEs had antiproliferative activity in HCC cell lines; of all the MEs studied, Fraxini has the most potent antiproliferative activity
Summary
The global incidence of hepatocellular carcinoma (HCC) has steadily risen in the last two decades[1,2,3,4,5]. MYCC, together with MYCL and MYCN, are the most commonly overexpressed genes in human cancer, and MYCC expression is highly regulated and closely linked to cell growth, apoptosis, and differentiation[12,13]. Both hepatitis B and C virus genes can potentiate c-Myc-induced tumorigenesis in transgenic mice, and the c-Myc www.nature.com/scientificreports/. Small molecules have been developed to target the CMYC oncogene, to date these agents have not been approved clinically[22] These studies suggest that a pharmaceutically tractable c-Myc targeting approach would represent a novel treatment paradigm for HCC patients. The molecular mechanisms associated with Fraxini’s anticancer activity in HCC are largely unknown
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