Xanthohumol inhibits Notch signaling and induces apoptosis in hepatocellular carcinoma

• Published in: PloS one Vol. 10; no. 5; p. e0127464
• Main Authors: Kunnimalaiyaan, Selvi, Sokolowski, Kevin M, Balamurugan, Mariappan, Gamblin, T Clark, Kunnimalaiyaan, Muthusamy
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 26.05.2015; Public Library of Science (PLoS)
• Subjects: Apoptosis; Apoptosis - drug effects; Bioavailability; Biotechnology; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Care and treatment; Caspase; Caspase-3; Cell cycle; Cell growth; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Cellular signal transduction; Colonies; Cyclin D1; Ectopic expression; FDA approval; Flavonoids; Flavonoids - pharmacology; Food; Forming; Health aspects; Hepatocellular carcinoma; Humans; Humulus lupulus; Ligands; Liver cancer; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Lysates; Mcl-1 protein; Medical research; Metastasis; Notch protein; Notch1 protein; Nutrition; Oncology; Pharmacokinetics; Pharmacology; Poly(ADP-ribose) polymerase; Propiophenones - pharmacology; Prostate; Proteins; Receptors, Notch - metabolism; Signal transduction; Signal Transduction - drug effects; Signaling; Surgery; Survivin; Tumor Stem Cell Assay; Xanthohumol; United States
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0127464

Despite improvement in therapeutic strategies, median survival in advanced hepatocellular carcinoma (HCC) remains less than one year. Therefore, molecularly targeted compounds with less toxic profiles are needed. Xanthohumol (XN), a prenylated chalcone has been shown to have anti-proliferative effects in various cancers types in vitro. XN treatment in healthy mice and humans yielded favorable pharmacokinetics and bioavailability. Therefore, we determined to study the effects of XN and understand the mechanism of its action in HCC. The effects of XN on a panel of HCC cell lines were assessed for cell viability, colony forming ability, and cellular proliferation. Cell lysates were analyzed for pro-apoptotic (c-PARP and cleaved caspase-3) and anti-apoptotic markers (survivin, cyclin D1, and Mcl-1). XN concentrations of 5 μM and above significantly reduced the cell viability, colony forming ability and also confluency of all four HCC cell lines studied. Furthermore, growth suppression due to apoptosis was evidenced by increased expression of pro-apoptotic and reduced expression of anti-apoptotic proteins. Importantly, XN treatment inhibited the Notch signaling pathway as evidenced by the decrease in the expression of Notch1 and HES-1 proteins. Ectopic expression of Notch1 in HCC cells reverses the anti-proliferative effect of XN as evidenced by reduced growth suppression compared to control. Taken together these results suggested that XN mediated growth suppression is appeared to be mediated by the inhibition of the Notch signaling pathway. Therefore, our findings warrants further studies on XN as a potential agent for the treatment for HCC.