Beta-glycosides are compounds consisting of sugar molecules attached to a functional group, such as flavonoids, phenolics, steroids, thiols, and nitriles, through glycosidic bonds. They are hydrolyzed by β-glucosidases (GBA)and changed to bioactive aglycones. Cancer cells are reported to have a higher concentration of extracellular GBA than normal cells. Moreover, the enzymes are known to be mutated in various types of cancer and hence, cancer tissues can be affected selectively by aglycons release through GBA action on glycosides. Glycosides have been reported to exhibit cytotoxic activity against several different cancer types, but studies concerning the GBA action of cancer on the glycosides are lacking. In this study, we investigated the effects of β-glycosides on GBA and autophagy of cancer cells. The results of the cell function assays revealed that digitoxin, a steroid glycoside, inhibited the proliferation of Li-7 (hepatoma) cells. Similar effect of diosgenin (aglycon) and dioscin (glycoside) was also observed in A172 (glioblastoma) cells. Autolysosome formation activities were particularly strong in A172 cultures treated by steroid glycosides, Li-7 treated by digitoxin, and CACO-2 (colon carcinoma) treated by glycosyl ceramide (glycoside).Extracellular GBAs were induced in A172 and Li-7 cells cultured in the presence of steroid glycosides. The observed growth inhibitory effect of dioscin is likely mediated by cell surface receptors, because no degradation of dioscin caused by the GBA from A172 cell, while digitoxin inducing extracellular GBA and degraded by the GBA of Li-7 might be mediated by intracellular receptors. The present study should provide the basis for investigating the potential of glycoside prodrugs to treat cancer with selectivity.
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