ursodoxicoltaurine and Pancreatic-Neoplasms

Pachymic acid (PA) is a purified triterpene extracted from medicinal fungus Poria cocos. In this paper, we investigated the anticancer effect of PA on human chemotherapy resistant pancreatic cancer. PA triggered apoptosis in gemcitabine-resistant pancreatic cancer cells PANC-1 and MIA PaCa-2. Comparative gene expression array analysis demonstrated that endoplasmic reticulum (ER) stress was induced by PA through activation of heat shock response and unfolded protein response related genes. Induced ER stress was confirmed by increasing expression of XBP-1s, ATF4, Hsp70, CHOP and phospho-eIF2α. Moreover, ER stress inhibitor tauroursodeoxycholic acid (TUDCA) blocked PA induced apoptosis. In addition, 25 mg kg-1 of PA significantly suppressed MIA PaCa-2 tumor growth in vivo without toxicity, which correlated with induction of apoptosis and expression of ER stress related proteins in tumor tissues. Taken together, growth inhibition and induction of apoptosis by PA in gemcitabine-resistant pancreatic cancer cells were associated with ER stress activation both in vitro and in vivo. PA may be potentially exploited for the use in treatment of chemotherapy resistant pancreatic cancer.

Topics: Activating Transcription Factor 4; Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Deoxycytidine; DNA-Binding Proteins; Drug Resistance, Neoplasm; Endoplasmic Reticulum Stress; Eukaryotic Initiation Factor-2; Female; Gemcitabine; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; HSP70 Heat-Shock Proteins; Humans; Mice; Mice, Nude; Pancreas; Pancreatic Neoplasms; Poria; Regulatory Factor X Transcription Factors; Signal Transduction; Taurochenodeoxycholic Acid; Transcription Factor CHOP; Transcription Factors; Triterpenes; Unfolded Protein Response; X-Box Binding Protein 1; Xenograft Model Antitumor Assays

The aim of this study was to examine whether tauroursodeoxycholate (TUDC) and cholestyramine resin (CR) enhance biliary carcinogenesis in the hamster model. A cholecystoduodenostomy with dissection of the extrahepatic bile duct on the distal end of the common duct was performed on Syrian hamsters. The hamsters were then divided randomly into 3 groups: control group, TUDC-treated group, and CR-treated group. All animals received N-nitrosobis(2-oxopropyl)amine (BOP) to initiate pancreaticobiliary cancer. The experiment was terminated at week 16 and the number of neoplastic lesions was counted microscopically. In the TUDC group, the intrahepatic biliary carcinogenesis was more accelerated than that observed in the control group, but no promoting effect was seen in the pancreas, gallbladder, or extrahepatic bile duct. In the CR group, both the intrahepatic biliary and the gallbladder carcinogenesis were inhibited compared with that observed in the control group and the TUDC group. TUDC enhanced the intrahepatic bile duct carcinogenesis, whereas CR inhibited both the intrahepatic bile duct and the gallbladder carcinoma. Bile acids were suggested to promote biliary carcinoma in the hamster model.

Topics: Administration, Oral; Animals; Anion Exchange Resins; Biliary Tract Neoplasms; Carcinogens; Cholagogues and Choleretics; Cholestyramine Resin; Cricetinae; Drug Synergism; Female; Isomerism; Mesocricetus; Nitrosamines; Pancreatic Neoplasms; Taurochenodeoxycholic Acid; Time Factors