» Articles » PMID: 21351272

Differential Interactions Between Statins and P-glycoprotein: Implications for Exploiting Statins As Anticancer Agents

Overview
Journal Int J Cancer
Specialty Oncology
Date 2011 Feb 26
PMID 21351272
Citations 26
Authors
Affiliations
Soon will be listed here.
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.

Citing Articles

ISTransbase: an online database for inhibitor and substrate of drug transporters.

Peng J, Yi J, Yang G, Huang Z, Cao D Database (Oxford). 2024; 2024.

PMID: 38943608 PMC: 11214160. DOI: 10.1093/database/baae053.


Repositioning of HMG-CoA Reductase Inhibitors as Adjuvants in the Modulation of Efflux Pump-Mediated Bacterial and Tumor Resistance.

Schelz Z, Muddather H, Zupko I Antibiotics (Basel). 2023; 12(9).

PMID: 37760764 PMC: 10525194. DOI: 10.3390/antibiotics12091468.


Mechanisms and Clinical Significance of Pharmacokinetic Drug Interactions Mediated by FDA and EMA-approved Hepatitis C Direct-Acting Antiviral Agents.

Murray M Clin Pharmacokinet. 2023; 62(10):1365-1392.

PMID: 37731164 DOI: 10.1007/s40262-023-01302-x.


Concurrent use of statins decreases major bleeding and intracerebral hemorrhage in non-valvular atrial fibrillation patients taking direct oral anticoagulants-A nationwide cohort study.

Wu H, Chang S, Lee T, Tu H, Liu C, Chang T Front Cardiovasc Med. 2022; 9:969259.

PMID: 36003918 PMC: 9393418. DOI: 10.3389/fcvm.2022.969259.


P-glycoprotein: new insights into structure, physiological function, regulation and alterations in disease.

Ahmed Juvale I, Abdul Hamid A, Abd Halim K, Che Has A Heliyon. 2022; 8(6):e09777.

PMID: 35789865 PMC: 9249865. DOI: 10.1016/j.heliyon.2022.e09777.