Chapter 3 - Immunomodulatory and Anticancer Activity of Sea Cucumber Triterpene Glycosides

Abstract

Abstract The triterpene glycosides are composed of a carbohydrate chain and triterpene aglycone and are widely distributed in sea cucumbers ( Holothurioidea , Echinodermata ). Most aglycones have 18(20)-lactones and belong to the holostane type. Carbohydrate chains of sea cucumber glycosides have from two to six monosaccharide residues including xylose, quinovose, glucose, and 3- O -methylglucose and sometimes 3- O -methylxylose, 3- O -methylquinovose, 3- O -methylglucuronic acid, and 6- O -acetylglucose. They may contain one, two, or three sulfate groups. At the milli- and micromolar concentrations, sea cucumber glycosides show hemolytic, cytotoxic, antifungal, and other biological activities caused by membranotropic action. The basis of membranotropic action of the glycosides is their ability to attach to cell biomembranes and form nonselective ion-conducting complexes with 5(6)-nonsaturated sterol components of cell membranes, preferably with cholesterol. Such sterol/saponin interactions result in an efflux of some ions, nucleotides, and peptides, disrupting ion homeostasis and osmolarity followed by lysis and cell death. Some sea cucumber glycosides show an immunostimulatory effect at subtoxic nanomolar concentrations. Incubation of immune cells with the glycosides induces their activation resulting in an increase of immune cell adhesion on an extracellular matrix, enhancement of cell spreading and motility, increase of macrophage lysosomal activity, ROS formation, and phagocytic activity. The most effective immunostimulants are monosulfated glycosides, whereas di- and trisulfated glycosides are immunodepressants. Injection of subtoxic doses of some glycosides induces an increase in the number of antibody-producing plaque-forming cells in mouse spleens, an increase in the number, size and acidity of lysosomes of peritoneal macrophages, and increase of phagocytic index, resulting in heightened resistance by host animals against bacterial infections. Proteomic methods have demonstrated that the mechanism of immunomodulatory action of some sea cucumber glycosides on mouse splenocytes includes regulation of the expression of some proteins involved in the formation of cellular immune response. These glycosides regulate the expression of proteins associated with lysosome maturation, activation and merging, phagocytosis, cytoskeletal reorganization, cell adhesion, mobility, and proliferation of immune cells. It was shown that glycosides moderately induce production of some cytokines, restore the level of some CD markers of lymphocytes, increase bactericidal activity of leukocytes, and induce a significant increase in mouse resistance to lethal doses of some pathogenic microorganisms and radiation. Cytotoxic activity of sea cucumber glycosides against different types of cells and cell lines, including human tumor cell lines, has been studied for many years. These studies have shown the triterpene glycosides block egg cleavage and development of sea urchin embryos, suppress the proliferation of various human tumor cell lines in vitro , possess antiangiogenic effect, and cause cancer cell cycle arrest. Several sea cucumber glycosides are reported to induce tumor cell apoptosis in vitro and more importantly, IP administration in rodents of solutions of some sea cucumber triterpene glycosides show significant reduction of both tumor burden and metastasis. Recently, it was found that the new immunomodulatory lead compound, Cumaside, based on the holothurian triterpene glycoside, cucumarioside A 2 -2, demonstrates inhibition of tumor initiation and proliferation, in vivo and exhibits significant synergy with 5-fluorouracil.