Differential interactions between statins and P-glycoprotein: implications for exploiting statins as anticancer agents
| Autor: | Carolyn A. Goard, Frances J. Sharom, Balpreet Vinepal, Anna Martirosyan, Paul C. Boutros, Linda Z. Penn, James W. Clendening, Richard G. Mather |
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| Rok vydání: | 2011 |
| Předmět: |
Cancer Research
Indoles Doxorubicin transport Atorvastatin Blotting Western Antineoplastic Agents Apoptosis Biology Pharmacology Fatty Acids Monounsaturated medicine Tumor Cells Cultured Humans Rosuvastatin Doxorubicin Pyrroles ATP Binding Cassette Transporter Subfamily B Member 1 Lovastatin Rosuvastatin Calcium Fluvastatin P-glycoprotein Cell Proliferation Ovarian Neoplasms Sulfonamides nutritional and metabolic diseases Drug Resistance Multiple Multiple drug resistance Fluorobenzenes Pyrimidines Oncology Drug Resistance Neoplasm Heptanoic Acids biology.protein lipids (amino acids peptides and proteins) Female Hydroxymethylglutaryl-CoA Reductase Inhibitors medicine.drug |
| Zdroj: | International journal of cancer. 127(12) |
| ISSN: | 1097-0215 |
| Popis: | Statins, prescribed for decades to control cholesterol, have more recently been shown to have promising anticancer activity. Statins induce tumor-selective apoptosis by inhibiting the mevalonate (MVA) pathway. In addition, we have recently demonstrated that lovastatin modulates drug accumulation in a MVA-independent manner in multidrug-resistant (MDR) tumor cells overexpressing the P-glycoprotein (P-gp) multidrug transporter. P-gp-mediated drug efflux can contribute to chemotherapy failure. However, direct statin-mediated inhibition of P-gp in human MDR tumor cells at clinically achievable concentrations remains unexplored. An understanding of these interactions is crucial, both to appreciate differences in the anticancer potential of different statins and to safely and effectively integrate statins into traditional chemotherapy regimens that include P-gp substrates. Here we evaluate interactions between 4 statins (lovastatin, atorvastatin, fluvastatin and rosuvastatin) and P-gp, at both the molecular level using purified P-gp and at the cellular level using human MDR tumor cells. Lovastatin bound directly to purified P-gp with high affinity and increased doxorubicin accumulation in MDR tumor cells, potentiating DNA damage, growth arrest and apoptosis. By contrast, while atorvastatin inhibited substrate transport by purified P-gp in proteoliposomes, it had no effect on doxorubicin transport in MDR tumor cells. Finally, fluvastatin and rosuvastatin only interacted with P-gp in vitro at high concentrations and did not inhibit doxorubicin transport in MDR cells. These differential interactions should be considered when combining statins with traditional chemotherapeutic drugs. |
| Databáze: | OpenAIRE |
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