TY - JOUR
T1 - Inhibition of cholangiocarcinoma growth by tannic acid
AU - Marienfeld, Carla
AU - Tadlock, Laura
AU - Yamagiwa, Yoko
AU - Patel, Tushar
N1 - Funding Information:
Abbreviations: TA, tannic acid; HPLC, high-performance liquid chromatography; MTS, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxy-methoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium; PBS, phosphate-buffered saline; AMC, 7-amino-4-methylcoumarin. From the Scott and White Clinic, Texas A&M University System Health Sciences Center, Temple, TX. Received September 9, 2002; accepted February 22, 2003. Supported by the Scott, Sherwood, and Brindley Foundation (C.M.), and grants DK60637 and DK02678 from the National Institutes of Health (T.P.). Address reprint requests to: Tushar Patel, M.D., Associate Professor of Internal Medicine, Division of Gastroenterology, Scott and White Clinic, Texas A&M University System Health Sciences Center, 2401 South 31st St., Temple, TX 76502. E-mail: tpatel@medicine.tamu.edu; fax: 254-724-8276. Copyright © 2003 by the American Association for the Study of Liver Diseases. 0270-9139/03/3705-0018$30.00/0 doi:10.1053/jhep.2003.50192
PY - 2003/5/1
Y1 - 2003/5/1
N2 - 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 mm3/d in mice fed with normal water to 5.5 ± 1.2 mm3/d in mice fed with water containing 0.05% TA. Pretreatment with 50 μg/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 p27KIP1. In addition, TA (0-50 μg/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.
AB - 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 mm3/d in mice fed with normal water to 5.5 ± 1.2 mm3/d in mice fed with water containing 0.05% TA. Pretreatment with 50 μg/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 p27KIP1. In addition, TA (0-50 μg/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.
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U2 - 10.1053/jhep.2003.50192
DO - 10.1053/jhep.2003.50192
M3 - Article
C2 - 12717390
AN - SCOPUS:0037698800
SN - 0270-9139
VL - 37
SP - 1097
EP - 1104
JO - Hepatology
JF - Hepatology
IS - 5
ER -