PT  - JOURNAL ARTICLE
AU  - Praveen K. Nambaru
AU  - Tobias Hübner
AU  - Kathleen Köck
AU  - Steffen Mews
AU  - Markus Grube
AU  - Léa Payen
AU  - Jérôme Guitton
AU  - Matthias Sendler
AU  - Gabriele Jedlitschky
AU  - Christian Rimmbach
AU  - Dieter Rosskopf
AU  - Dariusz W. Kowalczyk
AU  - Heyo K. Kroemer
AU  - Frank U. Weiss
AU  - Julia Mayerle
AU  - Markus M. Lerch
AU  - Christoph A. Ritter
TI  - Drug Efflux Transporter Multidrug Resistance-Associated Protein 5 Affects Sensitivity of Pancreatic Cancer Cell Lines to the Nucleoside Anticancer Drug 5-Fluorouracil
AID  - 10.1124/dmd.110.033613
DP  - 2011 Jan 01
TA  - Drug Metabolism and Disposition
PG  - 132--139
VI  - 39
IP  - 1
4099  - http://dmd.aspetjournals.org/content/39/1/132.short
4100  - http://dmd.aspetjournals.org/content/39/1/132.full
SO  - Drug Metab Dispos2011 Jan 01; 39
AB  - 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.