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.