Differential interactions between statins and P‐glycoprotein: Implications for exploiting statins as anticancer agents

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.

The Hedgehog Receptor Patched Functions in Multidrug Transport and Chemotherapy Resistance

“…In particular, Martirosyan and colleagues (36) recently showed that lovastatin induces apoptosis of ovarian cancer cells and synergizes with doxorubicin, which is used in the treatment of primary and relapsed drug-resistant ovarian cancer. Moreover, lovastatin has been shown to bind directly to the P-glycoprotein and to decrease doxorubicin accumulation in MDR tumor cells (48). Statins such as lovastatin inhibit cholesterol biosynthesis (49), and, therefore, decrease cholesterol intracellular concentration.…”

iASPP and Chemoresistance in Ovarian Cancers: Effects on Paclitaxel-Mediated Mitotic Catastrophe

“…On the other hand, recent studies showed the contribution of drug transporters as important mechanisms of chemoresistance in ovarian cancer (44,45). For example, as a primary efflux transporter, P-glycoprotein-mediated drug efflux could contribute to chemotherapy failure (45).…”

“…For example, as a primary efflux transporter, P-glycoprotein-mediated drug efflux could contribute to chemotherapy failure (45). To our best knowledge, there has been no report about the relationship between iASPP and drug transporters.…”

Targeting tumor cell metabolism with statins

“…One such effect that has recently been addressed is their capacity to interact with P-glycoprotein, a common multidrug transporter. 186,187 Strikingly, both lovastatin and atorvastatin interacted directly with P-glycoprotein in vitro and lovastatin also modulated multidrug resistance in tumor cells. Rosuvastatin and fluvastatin, by contrast, did not interact with P-glycoprotein at biologically relevant concentrations and did not impact tumor cell multidrug resistance.…”