Cholangiocarcinoma is an aggressive malignancy of the biliary tract for which effective treatment is lacking. Tannic acid (TA) is a naturally occurring polyphenolic compound with antioxidant and radical scavenging properties as well as anticarcinogenic effects. TA inhibited proliferation of malignant human cholangiocytes in vitro. Furthermore, the growth rate of Mz-ChA-1 cholangiocarcinoma xenografts in balb/c athymic mice was reduced from 10.9 +/- 1.8 mm(3)/d in mice fed with normal water to 5.5 +/- 1.2 mm(3)/d in mice fed with water containing 0.05% TA. Pretreatment with 50 microg/mL TA for 24 hours before xenograft implantation increased tumor latency by 2.5-fold compared with untreated controls, and decreased subsequent growth rates compared with controls in the absence of TA feeding. TA was not cytotoxic to Mz-ChA-1 cells in vitro, but enhanced sensitivity to camptothecin cytotoxicity. TA potently inhibited cell cycle progression, and increased expression of the cyclin-dependent kinase inhibitor p27(KIP1). In addition, TA (0-50 microg/mL) inhibited proteasomal activity in cholangiocyte cell extracts in a concentration-dependent manner. In conclusion, the growth inhibitory effects of TA may result from dysregulation of cell cycle progression due to altered proteasomal degradation of these cell cycle regulatory proteins. TA warrants evaluation as a candidate for the treatment of human cholangiocarcinoma either by itself or in combination with other chemotherapeutic agents.