Inhibitors of carbohydrate processing: A new class of anticancer agents.
There is a need for anticancer agents with novel mechanisms of action. Recently identified molecular targets for new anticancer agents include inducers of cell differentiation, cell cycle arrest, and apoptosis, as well as signaling pathways for growth factors and cytokines. Another unexplored opportunity is presented by the ubiquitous intracellular glycoprotein glycosylation pathway. This complex process, concerned with the addition of sugars onto newly synthesized proteins, occurs in the lumen of the rough endoplasmic reticulum and in the Golgi. There are estimates of over 200 glycosyltransferase enzymes in this pathway, which results in considerable structural diversity of carbohydrates found on secreted and transmembrane glycoproteins. The specificity of glycosyltransferases for acceptors and sugar-nucleotide donors dictates linkage positions between sugars, anomeric configuration of linkages, and monosaccharide composition. Specific carbohydrate structures participate in cell-cell and cell-substratum interactions affecting processes such as lymphocyte trafficking, immune cell stimulation, embryogenesis, and cancer metastasis. Of the carbohydrate-processing inhibitors presently available, the alkaloid swainsonine, a Golgi alpha-mannosidase II inhibitor, is the first to have been selected for clinical testing based on its anticancer activity, p.o. availability, and low toxicity in mice. Herein, we review the rationale for targeting Golgi carbohydrate processing pathways in the treatment of cancer, and summarize the preclinical and clinical results with swainsonine. Prospects for the development of second generation inhibitors with improved specificity for Golgi-processing enzymes are discussed. Potential clinical applications of this new class of anticancer agents are emphasized.
Goss
P E
PE
The Toronto Hospital, Department of Medical Oncology, Faculty of Medicine, University of Toronto, Ontario, M4X 1K9, Canada.
Baker
M A
MA
Carver
J P
JP
Dennis
J W
JW
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D050260:Carbohydrate Metabolism; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D017321:Clinical Trials, Phase I as Topic; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006023:Glycoproteins / Q000378:metabolism*; D006031:Glycosylation / Q000187:drug effects; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D008361:Mannosidases / Q000037:antagonists & inhibitors; D051379:Mice; D009154:Mutation; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000737:chemistry; D017026:Swainsonine / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000378:metabolism; D043323:alpha-Mannosidase
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D009363:Neoplasm Proteins; D008361:Mannosidases; D043323:alpha-Mannosidase; D017026:Swainsonine