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Differential interactions between statins and P-glycoprotein: implications for exploiting statins as anticancer
Carolyn A Goard1, Richard G Mather, Balpreet Vinepal
1Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
Abstract:
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.
Insights
Lovastatin directly inhibits P-glycoprotein (P-gp) in multidrug-resistant (MDR) cancer cells, enhancing chemotherapy. Other statins showed limited or no P-gp interaction, highlighting differential effects for combination therapy.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Statins, known for cholesterol management, exhibit anticancer properties by inducing tumor cell apoptosis via the mevalonate pathway.
- Multidrug resistance (MDR) in cancer, often mediated by P-glycoprotein (P-gp) efflux pumps, limits chemotherapy efficacy.
- Lovastatin has shown MVA-independent modulation of drug accumulation in MDR cells, suggesting direct interaction with P-gp.
Purpose of the Study:
- To investigate the direct interaction of four statins (lovastatin, atorvastatin, fluvastatin, rosuvastatin) with P-gp.
- To evaluate the impact of these statins on P-gp-mediated drug efflux in human MDR tumor cells at clinically relevant concentrations.
- To understand how statin-P-gp interactions influence the efficacy of chemotherapy drugs that are P-gp substrates.
Main Methods:
- In vitro studies using purified P-gp to assess direct binding and inhibition kinetics.
- Cell-based assays using human MDR tumor cells to measure drug accumulation (doxorubicin) and downstream effects (DNA damage, apoptosis).
- Proteoliposome-based transport assays to evaluate P-gp substrate inhibition by statins.
Main Results:
- Lovastatin demonstrated high-affinity direct binding to purified P-gp and significantly increased doxorubicin accumulation in MDR cells, enhancing cytotoxic effects.
- Atorvastatin inhibited P-gp substrate transport in proteoliposomes but showed no effect on doxorubicin transport in MDR cells.
- Flustvastatin and rosuvastatin exhibited minimal interaction with P-gp in vitro, even at high concentrations, and did not affect doxorubicin transport in MDR cells.
Conclusions:
- Lovastatin directly inhibits P-gp, offering a potential strategy to overcome MDR and enhance chemotherapy efficacy.
- Differential interactions of statins with P-gp necessitate careful consideration when integrating them into combination chemotherapy regimens.
- Understanding these specific drug-transporter interactions is crucial for optimizing cancer treatment strategies involving statins and P-gp substrate drugs.
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