Cyclooxygenase-2 inhibitors prevent the development of chemoresistance phenotype in a breast cancer cell line by inhibiting glycoprotein p-170 expression.
Breast cancer cells are usually sensitive to several chemotherapeutic regimens, but they can develop chemoresistance after prolonged exposure to cytotoxic drugs, acquiring a more aggressive phenotype. Drug resistance might involve the multi-drug resistance (MDR) 1 gene, encoding a transmembrane glycoprotein p-170 (P-gp), which antagonizes intracellular accumulation of cytotoxic agents, such as doxorubicin. We previously demonstrated that type 2 cyclooxygenase (COX-2) inhibitors can reverse the chemoresistance phenotype of a medullary thyroid carcinoma cell line by inhibiting P-gp expression and function. The aim of our study was to investigate the role of COX-2 inhibitors in modulating chemoresistance in a human breast cancer cell line, MCF7. MCF7 cells, expressing COX-2 but not MDR1, were treated with increasing doses of doxorubicin, and they became chemoresistant after 10 days of treatment, in association with MDR1 expression induction. This effect was reversed by doxorubicin withdrawal and prevented by co-incubation with N-[2-(cyclohexyloxy)4-nitrophenyl]-methanesulfonamide (NS-398), a selective COX-2 inhibitor. Treatment with NS-398 alone did not influence cell viability of a resistant MCF7 cell clone (rMCF7), but sensitized rMCF7 cells to the cytotoxic effects of doxorubicin. Moreover, treatment with NS-398 significantly reduced MDR1 expression in rMCF7 cells. Doxorubicin-induced membrane P-gp expression and function was also greatly impaired. Our data therefore support the hypothesis that COX-2 inhibitors can prevent or reduce the development of the chemoresistance phenotype in breast cancer cells by inhibiting P-gp expression and function.
Section of Endocrinology, Department of Biomedical Sciences and Advanced Therapies, University of Ferrara, Via Savonarola 9, 44100 Ferrara, Italy.
Maria Chiara
MC
Zatelli
Andrea
A
Luchin
Federico
F
Tagliati
Stefania
S
Leoni
Daniela
D
Piccin
Marta
M
Bondanelli
Roberta
R
Rossi
Ettore C
EC
degli Uberti
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000235:genetics*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000633:toxicity; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D009578:Nitrobenzenes / Q000494:pharmacology*; D010641:Phenotype; D012334:RNA, Neoplasm / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology*
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D006023:Glycoproteins; D009578:Nitrobenzenes; D012334:RNA, Neoplasm; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D004317:Doxorubicin; D051546:Cyclooxygenase 2