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Differential interactions between statins and P‐glycoprotein: Implications for exploiting statins as anticancer agents
Author(s) -
Goard Carolyn A.,
Mather Richard G.,
Vinepal Balpreet,
Clendening James W.,
Martirosyan Anna,
Boutros Paul C.,
Sharom Frances J.,
Penn Linda Z.
Publication year - 2010
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.25295
Subject(s) - rosuvastatin , atorvastatin , lovastatin , fluvastatin , doxorubicin , p glycoprotein , pharmacology , statin , efflux , apoptosis , hmg coa reductase , pravastatin , cancer research , chemotherapy , multiple drug resistance , chemistry , medicine , cholesterol , simvastatin , biochemistry , reductase , enzyme , antibiotics
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.