Xanthohumol, a Prenylated Chalcone Derived from Hops, Inhibits Growth and Metastasis of Melanoma Cells

Abstract

Melanoma is one of the most aggressive and lethal cancers worldwide. Despite recent progress in melanoma therapy, the prognosis for metastasized melanoma continues to be poor. Xanthohumol (XN), a prenylated chalcone derived from hop cones, is known to possess a broad spectrum of chemopreventive and anticancer activities. However, few studies have analyzed functional XN effects on melanoma cells and there have been no previous in vivo studies of its effects on metastasis. The aim of this study was to investigate the impact of XN on the tumorigenic and liver metastatic activity of melanoma cells. XN exhibited dose-dependent cytotoxic effects on human melanoma cell lines (Mel Ju; Mel Im) in vitro. Functional analysis in the subtoxic dose-range revealed that XN dose-dependently inhibited proliferation, colony formation, and migratory activity of melanoma cells. Subtoxic XN doses also induced markers of endoplasmic reticulum stress but inhibited the phosphorylation of the protumorigenic c-Jun N-terminal kinases (JNK). Furthermore, XN effects on hepatic metastasis were analyzed in a syngeneic murine model (splenic injection of murine B16 melanoma cells in C57/BL6 mice). Here, XN significantly reduced the formation of hepatic metastasis. Metastases formed in the liver of XN-treated mice revealed significantly larger areas of central necrosis and lower Ki67 expression scores compared to that of control mice. In conclusion, XN inhibits tumorigenicity of melanoma cells in vitro and significantly reduced hepatic metastasis of melanoma cells in mice. These data, in conjunction with an excellent safety profile that has been confirmed in previous studies, indicate XN as a promising novel agent for the treatment of hepatic (melanoma) metastasis.

Xanthohumol for Human Malignancies: Chemistry, Pharmacokinetics and Molecular Targets

“…XH suppressed migratory activity, proliferation, and formation of colonies. XH also decreased the liver metastasis of murine B16 melanoma cells in C57/BL6 mice and has evolved as an important chemotherapeutic agent for hepatic metastasis of melanoma treatment [ 106 ]. The anti-melanogenesis effect of XH was also studied on human keratinocytes (HacaT) for melanosome degradation, and in normal human melanocytes and MNT-1 human melanoma cells for its anti-melanogenesis effect.…”

Xanthohumol from Hop: Hope for cancer prevention and treatment

“…XN is a prenylated flavonoid extracted from the Hop plant Humulus lupulus L., (Figure 1a) which form an essential ingredient of beer. [63][64][65] XN exists ubiquitously in the Hop plant and is a component of the secreted resin from female inflorescences and through the glandular trichromes present on the cone bracts of hop plants. 63,66 The young leaves of the Hop plant also form as the source for XN.…”

“…For instance, it inhibited cell proliferation and metastasis in melanoma and hepatocellular carcinoma. 64 Furthermore, XN inhibited the proliferation, differentiation, and overproduction of cardiac fibroblast induced by TGF-β1 through modulating phosphatase and tensin homolog (PTEN)/Akt/mammalian target of rapamycin (mTOR) pathway. 76 XN was also reported to inhibit extracellular signal-regulated kinase 1/2 (ERK1/2) pathway and FOS-related antigen 1 (Fra1) that lead to inhibition of activator protein-1 (AP-1) transcription and also decreased cyclin D1 in non-small cell lung cancer (NSCLC) cells.…”

“…Xanthohumol (XN) is one such agent that has high potential in the prevention and treatment of several diseases, including cancer. XN is a prenylated flavonoid extracted from the Hop plant Humulus lupulus L., (Figure 1a) which form an essential ingredient of beer 63–65 . XN exists ubiquitously in the Hop plant and is a component of the secreted resin from female inflorescences and through the glandular trichromes present on the cone bracts of hop plants 63,66 .…”

“…The compound, XN, has shown several remarkable therapeutic potential in the prevention and treatment of several diseases. For instance, it inhibited cell proliferation and metastasis in melanoma and hepatocellular carcinoma 64 . Furthermore, XN inhibited the proliferation, differentiation, and overproduction of cardiac fibroblast induced by TGF‐β1 through modulating phosphatase and tensin homolog (PTEN)/Akt/mammalian target of rapamycin (mTOR) pathway 76 .…”