l-685458 and Liver-Neoplasms

Current studies are ongoing to find new drugs for the treatment of hepatocellular carcinoma (HCC). The discovery of drugs depends on the identification of molecules that can play essential roles in the development of liver cancer, for example, Notch pathway molecules. γ-Secretase inhibitors (GSIs) can inhibit the cleavage of intramembranous substrates of all Notch receptors and subsequently suppress Notch signaling. However, whether the inhibition of the Notch pathway can suppress or promote HCC growth is still under debate. In this study, we examined the expression of Notch pathway molecules in 20 pairs of HCC tissue with their normal counterparts and a panel of eight HCC cell lines. We also determined the effects of different types of GSI treatments on the cell growth of those HCC cell lines. Our results showed that the molecules of the Notch pathway were expressed in six of the eight HCC cell lines. Those six HCC cell lines were more sensitive to GSI-I treatment than the nonexpression ones. Among the four inhibitors, GSI-X and GSI-XXI exerted no effect on HCC cells growth at all. GSI-IX inhibited the growth of four HCC cell lines at 40 μmol/l. In contrast, most of these HCC cell lines were susceptible to a low concentration of GSI-I (1.2 μmol/l) treatment. The suppressive effect of GSI-I on cell growth was because of the inhibition of C-Myc, a Notch target gene. In addition, 80% (16/20) of the specimens showed either an increased expression of at least one Notch receptor or an augmented expression of Jagged1 compared with their normal counterparts. Our study reports for the first time that different kinds of GSIs can block the growth of several HCC cell lines. Our finding suggests that GSI-I is a potential chemical reagent and warrants additional testing in liver cancer therapeutics.

Topics: Amyloid Precursor Protein Secretases; Antineoplastic Agents; Basic Helix-Loop-Helix Transcription Factors; Benzodiazepinones; Calcium-Binding Proteins; Carbamates; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dipeptides; Gene Expression Regulation, Neoplastic; Genes, myc; Hep G2 Cells; Homeodomain Proteins; Humans; Intercellular Signaling Peptides and Proteins; Jagged-1 Protein; Liver Neoplasms; Membrane Proteins; Oligopeptides; Receptors, Notch; Serrate-Jagged Proteins; Transcription Factor HES-1