Glycosidases in cancer and invasion

Abstract

Glycosidases have been demonstrated to be elevated in the interstitial fluid of tumors, sera of animals and patients with tumors, and in some tumor tissue as compared to normal adjacent tissue. Elevations of serum beta-N-acetylglucosaminidase and beta-glucuronidase most commonly have been found to occur and these enzymes have been shown to be secreted into the extracellular medium by many different tumor cell types in vitro. The mechanism of cellular release of these hydrolytic enzymes probably involves tumor lysosomal exocytosis. Increased tumor glycosidase levels may promote increased tumor cell shedding from primary tumors, local invasion and perhaps be responsible directly, or indirectly for structural changes in tumor cell surface glycoconjugates. These cell surface changes could facilitate tumor cell thrombus formation, secondary site implantation and attachment in the microcirculation to endothelial cells and/or subendothelial basement membrane components. Other studies have demonstrated a correlation between metastatic cell potential and increased endoglycosidase and polysaccharide lyase activity. Generally, metastatic tumor cell variants have been found to be more invasive and capable of degrading proteoglycan basement membrane components, in part due to these increased levels of degradative enzymes. Hence, it is of considerable interest to develop inhibitors against these enzymes. Initial studies with glucuronidase inhibitors in the therapy of bladder tumors have been promising and with the advent of better agents and the use of appropriate in vitro metastatic models it may be possible to design and develop agents which interfere in various metastatic events and limit tumor progression.

Blockade of four-transmembrane L6 family member 5 (TM4SF5)-mediated tumorigenicity in hepatocytes by a synthetic chalcone derivative

“…Thus, there was considerable interest in the development of glycosidase inhibitors. 29 Characteristic oligosaccharide structures and their arrangements on tumor-associated membrane glycoprotein receptors may lead to tumor vaccine developments. 30 The p-toluenesulfonylamido and 4-hydroxy groups of TSAHC may target a sequence and/or N-linked carbohydrates unique to the EC2 loop of TM4SF5 that is responsible for intramolecular and intermolecular interactions, 11 presumably causing abnormal reorganization of membrane receptors including integrins in TERMs.…”

.ALPHA.-Glucosidase Inhibitors with a 4,5,6,7-Tetrachlorophthalimide Skeleton Pendanted with a Cycloalkyl or Dicarba-closo-dodecaborane Group.

“…21) In addition, the far more potent activity of 7 than 5 or 6 suggests that a compact hydrophobic structure with a certain bulkiness is important for the activity. Therefore, we designed conformationally restricted ring-expanded derivatives (8,9), and the compounds with a spherical hydrophobic substituent, i.e., adamantaneand carborane-pendanted derivatives (10, 11, respectively).…”

“…[8][9][10] Recently, effectiveness of a-glucosidase inhibitors in the treatment of B-and C-type viral hepatitis has been reported. 11,12) Several low-molecular-weight a-glucosidase inhibitors have been identified as a result of screening of natural products.…”

Biosynthesis and Biological Activity of Carbasugars

“…These compounds have been shown to be strong inhibitors of -L-fucosidase. -Fucosidase inhibitors are interesting because they are potential candidates for cancer and HIV drugs, due to their inhibitory effect on the extracellular matrix secreted fucosidases [358]. Different N-substituted derivatives of (±)-169 were prepared.…”