Xanthohumol, a prenylated chalcone derived from hops (Humulus lupulus), inhibits hepatic metastasis

In many cancer entities, including melanoma, hepatic metastasis is the critical factor determining tumor associated mortality. Xanthohumol, a prenylated chalcone derived from hope cones, is known to possess a broad spectrum of chemopreventive and anticancer activities. However, its functional effect on melanoma cells had not been analyzed and no in vivo studies of Xanthohumol effects on metastasis of any tumor entity existed. The aim of this study was to analyze the effect of Xanthohumol on (hepatic) metastasis of melanoma cells. Methods: Functional effects of Xanthohumol on proliferation and migration of human melanoma cell lines MelJu, MelIm and SKMel12 were analyzed in vitro. Furthermore, Xanthohumol effects on hepatic metastasis were analyzed in a syngeneic murine model (splenic injection of murine b16 melanoma cells in C57/BL6 mice). Xanthohumol was applied via subcutanously implanted pellets (Innovative Research of America, Sarasota, USA), releasing Xanthohumol continuously over time with a daily dose of 10 mg/kg body weight. Control mice received control pellets. In addition to macroscopic and histological analysis of the livers, expression of MIA, a gene specifically expressed in melanoma cells, was analyzed to measure hepatic metastasis. Results: Initially, we analyzed the effect of Xanthohumol on human melanoma cell lines in vitro. Here, Xanthohumol exhibited dose-dependent cytotoxic effects on melanoma cells beginning in the dose-range of 10 – 20µM. Notably, incubation with more than 10-fold higher Xanthohumol concentrations did not affect the viability of primary human hepatocytes in vitro. Functional analysis revealed that incubation with Xanthohumol in the subtoxic range dose-dependently inhibited proliferation and migration of melanoma cells in vitro. In the in vivo model, liver weight and hepatic MIA expression were significantly lower in Xanthohumol treated mice. Furthermore, size of tumors formed in the liver of Xanthohumol treated mice was smaller and they revealed significantly larger areas of central necrosis compared to control mice.