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P-Glycoprotein Mediates Celecoxib-Induced Apoptosis in Multiple Drug-Resistant Cell Lines

¹ Department of Internal Medicine, Postgraduate School in Oncology, Interuniversity Center for Liver Pathophysiology, University of Florence, Azienda Ospedaliero-Universitaria Careggi and Istituto Toscano Tumori, Florence, Italy and ² Department of Chemical, Food, Pharmaceutical and Pharmacological Sciences, University of East Piedmont "Amedeo Avogadro," Novara, Italy

Requests for reprints: Roberto Mazzanti, Department of Internal Medicine, Interuniversity Center for Liver Pathophysiology, Azienda Ospedaliero-Universitaria Careggi, Viale G.B. Morgagni 85, I.50134 Florence, Italy. Phone: 39-55-4296471; Fax: 39-55-4296468; E-mail: mazzanti-lab{at}dmi.unifi.it.

In several neoplastic diseases, including hepatocellular carcinoma, the expression of P-glycoprotein and cyclooxygenase-2 (COX-2) are often increased and involved in drug resistance and poor prognosis. P-glycoprotein, in addition to drug resistance, blocks cytochrome c release, preventing apoptosis in tumor cells. Because COX-2 induces P-glycoprotein expression, we evaluated the effect of celecoxib, a specific inhibitor of COX-2 activity, on P-glycoprotein–mediated resistance to apoptosis in cell lines expressing multidrug resistant (MDR) phenotype. Experiments were done using MDR-positive and parental cell lines at basal conditions and after exposure to 10 or 50 µmol/L celecoxib. We found that 10 µmol/L celecoxib reduced P-glycoprotein, Bcl-x_L, and Bcl-2 expression, and induced translocation of Bax from cytosol to mitochondria and cytochrome c release into cytosol in MDR-positive hepatocellular carcinoma cells. This causes the activation of caspase-3 and increases the number of cells going into apoptosis. No effect was shown on parental drug-sensitive or on MDR-positive hepatocellular carcinoma cells after transfection with MDR1 small interfering RNA. Interestingly, although inhibiting COX-2 activity, 50 µmol/L celecoxib weakly increased the expression of COX-2 and P-glycoprotein and did not alter Bcl-x_L and Bcl-2 expression. In conclusion, these results show that relatively low concentrations of celecoxib induce cell apoptosis in MDR cell lines. This effect is mediated by P-glycoprotein and suggests that the efficacy of celecoxib in the treatment of different types of cancer may depend on celecoxib concentration and P-glycoprotein expression. [Cancer Res 2007;67(10):4915–23]