Potential role of cyclooxygenase-2 on the regulation of the drug efflux transporter ABCG2 in breast cancer cell lines.
OBJECTIVE
ABCG2 (BCRP) implicated as a member of the multidrug resistance (MDR) proteins in tumors, mediating efflux of a wide spectrum of anticancer drugs. In recent years, there has been an increasing tendency toward the exploring of the potential link between cyclooxygenase-2 (COX-2) expression and development of multidrug resistance phenotype in patients with cancer. The aim of this study was to investigate the role of the COX-2 in modulating drug efflux by ABCG2 in a group of breast cancer cell lines.


METHODS
The cytotoxicity of COX-2 inducer (TPA, tetradecanoyl phorbol acetate) and its inhibitor (celecoxib) was determined by an MTT assay. ABCG2 activity was measured by flow cytometric mitoxantrone efflux assay.


RESULTS
TPA exhibited very little inhibitory activity in all cell lines, while long-term treatment with celecoxib significantly inhibited the growth of all cell lines. Furthermore, using mitoxantrone efflux assay was shown that TPA could increase ABCG2 activity in all the cell lines with the greatest stimulatory effects in MCF7-MX (more than 6 times the control level). It seemed that celecoxib inverted the effects of TPA on ABCG2 activity. This was more obvious in MCF7-MX.


CONCLUSIONS
The results suggest a probable causal link between COX-2 and ABCG2 activity. The use of celecoxib for adjuvant therapy in cancer treatment may contribute to decreased resistance to chemotherapeutic drugs transported by ABCG2.
Kalalinia
Fatemeh
F
Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. kalaliniaf831@mums.ac.ir
Elahian
Fatemeh
F
Behravan
Javad
J
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000187:drug effects / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D000068579:Celecoxib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D005434:Flow Cytometry; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008942:Mitoxantrone / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000187:drug effects / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate
C116614:ABCG2 protein, human; 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; D013449:Sulfonamides; D008942:Mitoxantrone; D051546:Cyclooxygenase 2; D000068579:Celecoxib; D013755:Tetradecanoylphorbol Acetate