ABSTRACT
D-Allose (D-All), a C-3 epimer of D-glucose (D-Glc), is a naturally rare monosaccharide, which shows anti-proliferative activity against several human cancer cell lines. Unlike conventional anticancer drugs, D-All targets glucose metabolism and is non-toxic to normal cells. Therefore, it has attracted attention as a unique "seed" compound for anticancer agents. However, the anti-proliferative activities of the other rare aldohexoses have not been examined yet. In this study, we evaluated the anti-proliferative activity of rare aldohexoses against human leukemia MOLT-4F and human prostate cancer DU-145 cell lines. We found that D-All and D-idose (D-Ido) at 5 mM inhibited cell proliferation of MOLT-4F cells by 46 % and 60 %, respectively. On the other hand, the rare aldohexoses at 5 mM did not show specific anti-proliferative activity against DU-145 cells. To explore the structure-activity relationship of D-Ido, we evaluated the anti-proliferative activity of D-sorbose (D-Sor), 6-deoxy-D-Ido, and L-xylose (L-Xyl) against MOLT-4F cells and found that D-Sor, 6-deoxy-D-Ido, and L-Xyl showed no inhibitory activity at 5 mM, suggesting that the aldose structure and the C-6 hydroxy group of D-Ido are important for its activity. Cellular glucose uptake assay and western blotting analysis of thioredoxin-interacting protein (TXNIP) expression suggested that the anti-proliferative activity of D-Ido is induced by inhibition of glucose uptake via TXNIP-independent pathway.
ABSTRACT
d-Allose, a C-3 epimer of d-glucose, is a naturally occurring rare monosaccharide that shows anti-proliferative activity against several human cancer cell lines. However, d-allose requires a relatively high concentration for the activity to be observed. Thus, developing more potent derivatives is needed for application. In cells, d-allose is converted to d-allose-6-phosphate (A6P), which is responsible for the anti-proliferative activity of d-allose. In this study, we synthesized A6P derivative 1 with biodegradable protecting groups, which showed higher anti-proliferative activity than A6P against a MOLT-4F human leukemia cell line. Similarly protected derivative of d-glucose-6-phosphate (G6P) (2) and tetraacetyl-A6P (3) showed weaker and less activity compared with 1, respectively, suggesting that both A6P moiety and the protecting group on the phosphate group are responsible for the activity. In addition, significantly weaker induction of thioredoxin-interacting protein (TXNIP) expression by 1 compared with d-allose suggests that 1 exhibited cytotoxicity through the synergetic effect of inducing TXNIP expression and other mechanisms.
