title: Tannic acid synergizes the cytotoxicity of chemotherapeutic drugs in human cholangiocarcinoma by modulating drug efflux pathways.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Internal Medicine, Scott and White Clinic, Texas A&M University System Health Science Center, College of Medicine Temple, TX 76508, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Naus
authors.forename: Roger
authors.initials: R
authors.lastname: Henson
authors.forename: Grant
authors.initials: G
authors.lastname: Bleeker
authors.forename: Hania
authors.initials: H
authors.lastname: Wehbe
authors.forename: Fanyin
authors.initials: F
authors.lastname: Meng
authors.forename: Tushar
authors.initials: T
authors.lastname: Patel
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D001650:Bile Duct Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000188:drug therapy*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D015536:Down-Regulation; D004347:Drug Interactions; D005452:Fluoresceins / Q000378:metabolism; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D026901:Membrane Transport Proteins / Q000378:metabolism; D016685:Mitomycin / Q000008:administration & dosage; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D013634:Tannins / Q000627:therapeutic use*; D000093542:Gemcitabine
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003841:Deoxycytidine; D005452:Fluoresceins; D005472:Fluorouracil; D026901:Membrane Transport Proteins; D016685:Mitomycin; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D013634:Tannins; D000093542:Gemcitabine; C000715087:ABCC2 protein, human; C007740:fluorexon; C421109:multidrug resistance-associated protein 1