PURPOSE: 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.
PURPOSE: 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.
Authors: George P Tegos; Annette M Evangelisti; J Jacob Strouse; Oleg Ursu; Cristian Bologa; Larry A Sklar Journal: Drug Discov Today Technol Date: 2014-06
Authors: Ka-Wing Cheng; Chi C Wong; George Mattheolabakis; Gang Xie; Liqun Huang; Basil Rigas Journal: Int J Oncol Date: 2013-06-27 Impact factor: 5.650
Authors: B S Vinod; J Antony; H H Nair; V T Puliyappadamba; M Saikia; S Shyam Narayanan; A Bevin; R John Anto Journal: Cell Death Dis Date: 2013-02-21 Impact factor: 8.469