Rare Sugar D-Allose Enhances Anti-tumor Effect of 5-Fluorouracil on the Human Hepatocellular Carcinoma Cell Line HuH-7

D-Allose is a novel anti-tumor monosaccharide that causes cell growth inhibition, specifically of the cancer cells, by inducing the tumor suppressor gene thioredoxin interacting protein (TXNIP). The commonly used anti-tumor drug, 5-fluorouracil (5-FU), blocks the cell cycle by inhibiting thymidylate synthase, and is also known to induce TXNIP gene expression. In this study, we examined the synergistic effect of D-allose and 5-FU and the role of TXNIP on cancer cell growth. The treatment of HuH-7 cells with D-allose or 5-FU inhibited the cell growth in a dose-dependent manner (75.2 +/- 2.70% with 50 mM D-allose and 66.1 +/- 2.7 with 0.5 mu g/ml 5-FU) and D-allose enhanced the anti-tumor effect of 5-FU (55.3 +/- 1.1%). TUNEL analysis did not show any evidence of apoptosis with either D-allose or 5-FU treatment. 5-FU suppressed the expression of p27(kip1), p53, and cyclin E, whereas D-allose induced p53 and reduced cyclins D, A, and E. The expression of p27(kip1) remained unchanged by D-allose at transcriptional level, but increased at the protein level suggesting an increase in protein stability by TXNIP. D-Allose and to a lesser extent 5-FU induced TXNIP expression significantly (808.4 +/- 122.9% and 186.8 +/- 32.9%, respectively) and the combination of both further enhanced TXNIP expression. As D-allose has no known side effects on normal cells, the combination of D-allose and 5-FU might be a potent candidate for cancer therapy.