P-Glycoprotein Mediates Celecoxib-Induced Apoptosis in Multiple Drug-Resistant Cell Lines
| Autor: | Ornella Fantappiè, Luciana Tessitore, Michela Solazzo, Nadia Lasagna, Roberto Mazzanti, Francesca Platini |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Cancer Research
medicine.medical_specialty Programmed cell death Small interfering RNA Carcinoma Hepatocellular bcl-X Protein Apoptosis Biology Mice Bcl-2-associated X protein Cell Line Tumor Internal medicine medicine Animals Humans ATP Binding Cassette Transporter Subfamily B Member 1 bcl-2-Associated X Protein P-glycoprotein Sulfonamides Liver Neoplasms Cytochromes c Transfection Drug Resistance Multiple Mitochondria Endocrinology Proto-Oncogene Proteins c-bcl-2 Oncology Celecoxib Cyclooxygenase 2 Cell culture NIH 3T3 Cells biology.protein Cancer research Pyrazoles HT29 Cells medicine.drug |
| Zdroj: | Cancer Research. 67:4915-4923 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-06-3952 |
| Popis: | 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-xL, 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-xL 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] |
| Databáze: | OpenAIRE |
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