Abstract
Pancreatic adenocarcinoma is one of the malignancies that is highly resistant to therapy and among the leading causes of cancer-related death. Several factors may influence pancreatic cancer resistance, and expression of ATP-binding cassette transport proteins is one of the major mechanisms of drug resistance. Members of this family's C-branch, also referred to as multidrug resistance-associated proteins (MRPs), might be of particular interest because they are able to efflux nucleoside analogs used in the treatment of pancreatic cancer. Expression of MRP1, MRP3, MRP4, and MRP5 in human pancreas and pancreatic carcinoma has been reported. However, contributions of MRPs to chemoresistance of pancreatic cancer are not fully understood. MRP5 mRNA expression in pancreatic adenocarcinoma cell lines correlated significantly with cellular sensitivity to 5-fluorouracil (5-FU) (r = 0.738, p < 0.05). Long-term treatment with 5-FU increased expression of MRP5 by 2.4-fold and was associated with significant drug resistance [IC50 values for control and 5-fluorouracil (5-FU)-resistant Patu-T cell lines were 11.3 ± 5.3 and 33.2 ± 6.9 μM, respectively (p < 0.05)]. Consequently, overexpression of MRP5 in Colo-357 cells resulted in significantly reduced accumulation of 5-FU related radioactivity and 5-FU cytotoxicity. Knockdown of MRP5 significantly increased cellular cytotoxicity of 5-FU to Patu-02 cells and enhanced accumulation of radioactivity related to 5-FU and its metabolites. Our results suggest that MRP5 is expressed and functionally active and contributes to variable sensitivities of pancreatic adenocarcinoma cell lines to 5-FU. Further investigations using models that resemble human pancreas tumors are necessary to prove a causative relation between expression and activity of MRP5 and tumor resistance to 5-FU.
Footnotes
- Received March 29, 2010.
- Accepted October 5, 2010.
This work was supported in part by the German Ministry for Education and Research [InnoProfile 03IP612]. P.K.N. received a stipend for the Graduate Program “Tumor Biology” of the Alfried Krupp College of Science, Greifswald, Germany, supported by the Alfried Krupp von Bohlen und Halbach-Foundation, Essen, Germany.
Parts of this work were previously presented at the following conference: Nambaru PK, Köck K, Rimmbach C, Weiss FU, Rosskopf D, Lerch MM, Kroemer HK, and Ritter CA (2008) Modulation of MRP4 and MRP5 expression affects sensitivity of pancreatic cancer cells to nucleoside analog anticancer agents. 10th European Regional Meeting of the International Society for the Study of Xenobiotics; 2008 May 18–21; Vienna, Austria. Drug Metab Rev 40 (Suppl 1):166–167. International Society for the Study of Xenobiotics, Washington, DC.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.033613.
ABBREVIATIONS:
- 5-FU
- 5-fluorouracil
- hENT
- human equilibrative nucleoside transporter
- MRP
- multidrug resistance protein
- ABC
- ATP-binding cassette
- 6-MP
- 6-mercaptopurine
- 6-TG
- 6-thioguanine
- 5-FdUrd
- 5′-fluoro-2′-deoxyuridine
- 5-FdUMP
- 5′-fluoro-2′-deoxyuridine monophosphate
- RT
- reverse transcription
- PCR
- polymerase chain reaction
- siRNA
- small interfering RNA
- GFP
- green fluorescent protein
- BCRP
- breast cancer resistance protein
- PBS
- phosphate-buffered saline
- PI
- propidium iodide
- MK571
- 3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid
- GEM
- gemcitabine.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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