Inhibition of experimental metastasis by castanospermine in mice: blockage of two distinct stages of tumor colonization by oligosaccharide processing inhibitors.
The extent of maturation of the oligosaccharide subunits of tumor cell glycoproteins appears to correlate with malignant potential, suggesting that modification of oligosaccharide structures may alter metastatic capacity. Castanospermine, a recently discovered inhibitor of glucosidase I, was tested for its effect on experimental metastasis of B16-F10 murine melanoma cells and was compared to treatment with swainsonine and tunicamycin. All three drugs block different steps in the pathway of glycoprotein processing yet each was a potent inhibitor of pulmonary colonization after i.v. injection of treated cells into C57BL/6 mice (greater than or equal to 80% inhibition). This result indicates a generality of inhibition of experimental metastasis by blockage of protein glycosylation or oligosaccharide processing and strongly implicates carbohydrate residues in at least one critical step of the metastatic cascade. Cytotoxic side effects could not account for the inhibitory activity. In order to identify a possible mechanism of inhibition of colonization, the adhesive behavior and pulmonary retention properties of B16-F10 cells treated with the above inhibitors were examined. Tunicamycin-treated B16-F10 cells exhibited poor adhesion to substrate-adsorbed fibronectin and laminin, whereas both castanospermine- and swainsonine-treated cells possessed near normal adhesive capacity; furthermore, the initial rate of loss of tunicamycin-treated cells from the lungs of mice was substantially greater than either control, castanospermine- or swainsonine-treated cells. These data suggest that these processing inhibitors can block experimental metastasis by at least two different mechanisms. The antimetastatic effect of tunicamycin may be related to interference in tumor cell-extracellular matrix interactions, whereas treatment with castanospermine or swainsonine appears to block at a stage distal to initial tumor cell arrest.
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005353:Fibronectins / Q000378:metabolism; D065089:Glycoside Hydrolase Inhibitors; D007212:Indolizines; D007797:Laminin / Q000378:metabolism; D008175:Lung Neoplasms / Q000556:secondary; D008545:Melanoma / Q000473:pathology; D051379:Mice; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009844:Oligosaccharides / Q000502:physiology*; D011487:Protein Conformation; D017026:Swainsonine; D014415:Tunicamycin / Q000494:pharmacology; D000520:alpha-Glucosidases; D054836:Indolizidines
D000470:Alkaloids; D005353:Fibronectins; D065089:Glycoside Hydrolase Inhibitors; D007212:Indolizines; D007797:Laminin; D009844:Oligosaccharides; D017026:Swainsonine; D014415:Tunicamycin; D000520:alpha-Glucosidases; C042059:glucosidase I; C037806:castanospermine; D054836:Indolizidines