• DOI:10.1158/0008-5472.CAN-06-3952
• Corpus ID: 8838797

P-glycoprotein mediates celecoxib-induced apoptosis in multiple drug-resistant cell lines.

@article{Fantappi2007PglycoproteinMC,
  title={P-glycoprotein mediates celecoxib-induced apoptosis in multiple drug-resistant cell lines.},
  author={Ornella Fantappi{\'e} and Michela Solazzo and Nadia Lasagna and Francesca Platini and Luciana Tessitore and Roberto Mazzanti},
  journal={Cancer research},
  year={2007},
  volume={67 10},
  pages={
          4915-23
        }
}

• O. Fantappié, M. Solazzo, +3 authors R. Mazzanti
• Published 15 May 2007
• Biology, Medicine
• Cancer research

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 micromol/L celecoxib. We found that 10 micromol/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 micromol/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.