Celecoxib upregulates multidrug resistance proteins in colon cancer: lack of synergy with standard chemotherapy.
Recent phase II randomised trials in colorectal cancer failed to demonstrate any advantage of celecoxib combined with standard chemotherapy; some authors even reported that the addition of celecoxib to irinotecan and oxaliplatin in colon cancer results in an inferior response rate. This observation leads to the hypothesis that there are pharmacokinetic interactions between celecoxib and chemotherapeutic drugs. The aim of the study was to investigate the induction by celecoxib of some multidrug resistance proteins, MRP1, MRP2, MRP4 and MRP5, involved in the transport of irinotecan and 5-FU. WiDr and COLO-205 cells were treated with celecoxib at a clinically relevant concentration. A viability assay was performed by treating cells with chemotherapy alone and chemotherapy plus celecoxib. The expression of MRP1, MRP2, MRP4 and MRP5 was analysed by RT-PCR and Western blot analysis. The sub cellular localization of MRP4 and MRP5 was investigated by cryoimmunoelectron microscopy. In both cell lines celecoxib induced MRP4 and MRP5 over-expression at RNA and protein levels. No induction of MRP1 and MRP2 was observed in treated cells compared to controls. Cryoimmunoelectron microscopy showed increased MRP4 and MRP5 immunolabeling in celecoxib treated cells both at cytoplasmic level and along the plasma membrane. Our findings suggest that the low response rate observed in clinical trials using celecoxib added to 5-fluorouracil and irinotecan may reflect celecoxib-mediated extrusion of chemotherapeutic drugs from cancer cells through the up regulation of ATP-binding cassette proteins. Our findings, together with the results of clinical trials, may suggest that the combined use of celecoxib and drugs that are substrate for MRP4/MRP5 should be avoided.
Gradilone
A
A
Department of Experimental Medicine, "Sapienza", University of Rome, Viale Regina Elena 324, 00161 Rome, Italy.
Pulcinelli
F M
FM
Lotti
L V
LV
Trifirò
E
E
Martino
S
S
Gandini
O
O
Gianni
W
W
Frati
L
L
Aglianò
A M
AM
Gazzaniga
P
P
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism*; D015153:Blotting, Western; D000068579:Celecoxib; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D003593:Cytoplasm / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007124:Immunoenzyme Techniques; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D011720:Pyrazoles / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013347:Subcellular Fractions; D013449:Sulfonamides / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D018435:ATP Binding Cassette Transporter, Subfamily B; D000068579:Celecoxib; D016861:Cyclooxygenase Inhibitors; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011720:Pyrazoles; D012333:RNA, Messenger; D013449:Sulfonamides; C000715087:ABCC2 protein, human; C073492:ABCC4 protein, human; C120809:ABCC5 protein, human; C421109:multidrug resistance-associated protein 1