calixarenes and Liver-Neoplasms

Galectins are beta-galactose specific binding proteins. In human cancers, including hepatocellular carcinoma (HCC), galectin-1 (Gal-1) is often found to be overexpressed. In order to combat the dismal diagnosis and death rates of HCC, gene silencing and targeted inhibition of Gal-1 was investigated for its improved therapeutic potential.. Cellular and secretory Gal-1 levels were analyzed using HCC clinical samples. The study of Gal-1 was carried by both knockdown and overexpression approaches. The stable clones were tested by in vitro assays and in vivo experiments. Mass spectrometry was used to identify downstream targets of Gal-1. The upstream regulator of Gal-1, microRNA-22 (miR-22) was characterized by functional assays. The therapeutic effect of inhibiting Gal-1 was also analyzed.. Gal-1 overexpression was observed in HCC and correlated with aggressive clinicopathological features and poorer survival. The loss of Gal-1 resulted in hindered cell migration, invasion and anchorage independent growth. This was also observed in the animal models, in that when Gal-1 was knocked down, there were fewer lung metastases. Proteomic profiling of control and Gal-1 knockdown cells identified that the level of retention in endoplasmic reticulum 1 (RER1) was suppressed when Gal-1 level was reduced. The cell motility of Gal-1 knockdown cells was enhanced upon the rescue of RER1 expression. In HCC tissues, Gal-1 and RER1 expressions displayed a significant positive correlation. The upstream regulator of Gal-1, miR-22 was observed to be underexpressed in HCC tissues and negatively correlated with Gal-1. Silencing of miR-22 resulted in the upregulation of Gal-1 and enhanced cell growth, migration and invasion. However, such enhancement was abolished in cells treated with OTX008, an inhibitor of Gal-1. Combinational treatment of OTX008 and sorafenib significantly reduced tumor growth and size.. Gal-1 overexpression was detected in HCC and this played a role in promoting tumorigenic processes and metastasis. The function of Gal-1 was found to be mediated through RER1. The correlations between miR-22, Gal-1 and RER1 expressions demonstrated the importance of miR-22 regulation on Gal-1/RER1 oncogenic activity. Lastly, the combinational treatment of OTX008 and sorafenib proved to be an improved therapeutic option compared to when administering sorafenib alone.

Topics: Animals; Calixarenes; Carcinoma, Hepatocellular; Galectin 1; Humans; Liver Neoplasms; Male; Mice; Mice, Nude; Sorafenib; Transfection

Despite the fact that a large number of synthetic channels have been developed in the last three decades, few of them can function in mammalian cell membranes because of their weak membrane insertion abilities. This study describes a tubular molecule with terminal positively charged amino groups that displays a strong ability to insert into lipid bilayers composed of phosphatidylcholine and consequently forming unimolecular transmembrane channels. It has been demonstrated that the insertion of the channel into the phosphatidylcholine bilayers was driven by the electrostatic interaction between the positively charged amino groups of the channel molecules and the negatively charged phosphate groups of the lipid molecules. The high affinity of the channels for lipid bilayers led to efficient mammalian cell membrane insertion. The channels showed high effective activity against HepG2 cancer cells at concentrations above 5.1 μM.

Topics: Animals; Antineoplastic Agents; Calixarenes; Cell Membrane; Cell Proliferation; Cell Survival; Drug Screening Assays, Antitumor; Erythrocytes; Hep G2 Cells; Humans; Lipid Bilayers; Liver Neoplasms; Optical Imaging; Rats; Staphylococcus epidermidis; Tumor Cells, Cultured