Tannic acid synergizes the cytotoxicity of chemotherapeutic drugs in human cholangiocarcinoma by modulating drug efflux pathways.

BACKGROUND/AIMS: Tannic acid is an orally active plant polyphenol with potential for use as an anti-cancer agent for cholangiocarcinoma. To determine the potential use of tannic acid as an adjunct therapy, we sought to evaluate the interaction between tannic acid and chemotherapeutic agents. METHODS: Cytotoxicity was assessed in malignant human cholangiocytes. Interactions between tannic acid, mitomycin C, 5-fluorouracil and gemcitabine were quantitated by calculating the combination index and dose reduction index. Cellular efflux pathways were assessed by calcein retention assays, and expression of membrane pumps was assessed by Western blots and real-time PCR. RESULTS: Tannic acid and the three agents decreased growth of malignant cholangiocytes to a similar extent. Tannic acid had a synergistic effect to mitomycin C and 5-fluorouracil, but not gemcitabine. However, the structurally related polyphenol gallic acid did not have a synergistic interaction with any of the agents. Tannic acid decreased calcein efflux and the expression of PGP, MRP1 and MRP2 membrane efflux pumps. CONCLUSIONS: Tannic acid has a synergistic effect with selected chemotherapeutic drugs by a mechanism involving modulation of drug efflux pathways. Thus, tannic acid will be a useful adjunct to improve the effectiveness of chemotherapeutic agents in the treatment of cholangiocarcinoma.

Cyclooxygenase-2 inhibitors: a painful lesson.

Non-steroidal anti-inflammatory drugs (NSAIDs) represent a clinically important class of agents. NSAIDs are commonly used in treatment of conditions such as headache, fever, inflammation and joint pain. Complications often arise from chronic use of NSAIDs. Gastrointestinal (GI) toxicity in the form of gastritis, peptic erosions and ulcerations and GI bleeds limit usage of NSAIDs. These toxicities are thought to be due to cyclooxygenase (COX)-1 blockade. COX-1 generates cytoprotective prostanoids such as prostaglandin (PG) E2 and prostacyclin (PGI2). COX-2 inhibitors, commonly referred to as coxibs, were developed to inhibit inflammatory prostanoids without interfering with production of COX-1 prostanoids. Concerns over cardiovascular safety, however, have evolved based on the concept of inhibition of COX-2-derived endothelial prostanoids without inhibition of platelet thromboxane A2, leading to increased cardiovascular risk. The Celecoxib Long-Term Arthritis Safety Study (CLASS) trial did not show a significant increase in cardiovascular risk for celecoxib (Celebrex), but results of the Vioxx Gastrointestinal Outcomes Research (VIGOR) study showed an increased cardiovascular risk with long-term daily usage of rofecoxib in patients with rheumatoid arthritis. The Adenomatous Poly Prevention on Vioxx (APPROVe) trial further evaluated cardiovascular effects of rofecoxib and recently led to removal of this drug from the marketplace. Coxibs affect renal function via blockade of normal COX-2 functions. COX-2 expression increases in high renin states and in response to a high-sodium diet or water deprivation. PGI2 and PGE2 are the most important renal prostanoids. PGI2 inhibition results in hyperkalemia. PGE2 inhibition results in sodium retention, which leads to hypertension, peripheral edema and potentially exacerbation of heart failure. This review article discusses beneficial and deleterious effects associated with prostanoids produced by COX-1 and COX-2 in various organs and how blockade of these products translates into clinical medicine.