Cyclooxygenase inhibitors down regulate P-glycoprotein in human colorectal Caco-2 cell line.
OBJECTIVE
Elevated expression of the ABC transporters P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP) seems to correlate with multidrug resistance of cancer cells. In this study we investigated the effect of COX inhibitors in modulating P-gp and BCRP expression and P-gp activity in Caco-2 cells.


METHODS
mRNA and protein expression of MDR1 and BCRP were evaluated by real time PCR and western blot respectively. The activity of P-gp was measured by intracellular accumulation of rhodamine123 or 3H-Digoxin.


RESULTS
The chronic exposure of Caco-2 to indomethacin heptyl ester (indo HE) (0.4 muM) or nimesulide (10 muM) (selective COX-2 inhibitors) and naproxen (6 muM) (non selective inhibitor COX-1/COX-2) significantly decreased the expression and activity of P-gp. In contrast, the acute treatment by nimesulide and naproxen did not modify these parameters while indo HE treatment (48-72 h) caused a protein decrease and a functional inhibition of P-gp. Unexpectedly, the short-term treatment with naproxen induced an important increase of BCRP expression, but this induction was lost after long-term treatment. No modification of BCRP expression was observed after indo HE or nimesulide treatment.


CONCLUSIONS
Our observations suggest a possible down regulation of P-gp by COX inhibitors, which may enhance the accumulation of chemotherapy agents.
Zrieki
Afraa
A
Université Paris-sud XI, Faculté de Pharmacie, Laboratoire de Pharmacie Clinique, UPRES EA 2706, Tour D1, 5ème étage, 5 rue Jean-Baptist Clément, Châtenay-Malabry, 92296, France. afraa.zrieki@u-psud.fr
Farinotti
Robert
R
Buyse
Marion
M
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018938:Caco-2 Cells; D000068579:Celecoxib; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007213:Indomethacin / Q000031:analogs & derivatives / Q000494:pharmacology; D009288:Naproxen / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D015203:Reproducibility of Results; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors
C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D009363:Neoplasm Proteins; D011720:Pyrazoles; D012333:RNA, Messenger; D013449:Sulfonamides; D009288:Naproxen; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D000068579:Celecoxib; D015232:Dinoprostone; C012655:nimesulide; D007213:Indomethacin