Modulatory effects of curcumin on multi-drug resistance-associated protein 5 in pancreatic cancer cells.
OBJECTIVE
Chemotherapy of pancreatic cancer often fails due to the development of intrinsic and acquired resistance during drug treatment. Recent studies have suggested that MRP5 conferred resistance to first-line drugs 5-fluorouracil and gemcitabine by active efflux of drugs from the cell. Our aim was to evaluate whether curcumin could reverse this multi-drug resistance by inhibition of MRP5-mediated efflux.


METHODS
MRP5 protein was detected and localized by immunocytochemistry using a monoclonal antibody in MRP5 over-expressing HEK293 (HEK293/MRP5) cells and two pancreatic cancer cell lines PANC-1 and MiaPaCa-2. The cellular accumulation of a specific MRP5 fluorescent substrate 2',7'-Bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF) into these cells was measured by flow cytometry and the cell proliferation determined by a 72-h CyQuant assay.


RESULTS
The cellular accumulation of BCECF in HEK293/MRP5 cells and in PANC-1 and MiaPaCa-2 cells was significantly increased by curcumin in a concentration-dependent manner. Curcumin and a MRP5 inhibitor MK571 had no apparent effects on cellular accumulation of BCECF in parental HEK293 cells. In the proliferation assays, curcumin caused a concentration-dependant increase in the sensitivity to the cytotoxic drug 5-fluorouracil in HEK293/MRP5 cells, PANC-1 and MiaPaCa-2 pancreatic cancer cells, but not in parental HEK293 cells.


CONCLUSIONS
Our results suggest that curcumin is an inhibitor of MRP5 and may be useful in the reversal of multi-drug resistance in pancreatic cancer chemotherapy.
Department of Pharmacology & Clinical Pharmacology, The University of Auckland, Auckland, New Zealand. yan.li@auckland.ac.nz
Yan
Y
Li
Jezrael L
JL
Revalde
Glen
G
Reid
James W
JW
Paxton
D016588:Anticarcinogenic Agents / Q000378:metabolism / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival; D003474:Curcumin / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D005452:Fluoresceins / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D005456:Fluorescent Dyes; D005472:Fluorouracil / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy*
D016588:Anticarcinogenic Agents; D000964:Antimetabolites, Antineoplastic; D003474:Curcumin; D005452:Fluoresceins; D005456:Fluorescent Dyes; D005472:Fluorouracil; D019833:Genistein; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C120809:ABCC5 protein, human; C043829:2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein; C004541:biochanin A