Drug delivery across the blood-brain barrier (BBB) limits the efficacy of pharmacological therapy of brain tumors. For instance the anticancer drug doxorubicin, that is effective in vitro, has a poor efficacy in vivo because it is extruded through several efflux pumps like P-glycoprotein (Pgp), multidrug resistance-related proteins (MRPs) and breast cancer resistance protein (BCRP), present at high levels on BBB cells.1 We have previously observed that the anticholesterolemic drug statins reduce the activity of the efflux pumps in solid tumors with a nitric oxide (NO)-dependent mechanism.2 In this work we analyzed the effects of two lipohilic statins, mevastatin and simvastatin, on drug transport at BBB level. In primary human cerebral microvascular endothelial HCMEC/D3 cells, statins decrease the synthesis of cholesterol and isoprenoids, impair the activity of the small G-protein Rho and of the downstream effector RhoA kinase. By doing so, statins activate the IKK/NF-kB pathway, up-regulate the NO synthase isoform II and produce the nitration of critical tyrosine residues on Pgp and BCRP, decreasing the ATP-ase activity. As result, doxorubicin, a drug that is fully extruded by HCMEC/D3 cells, becomes able to cross the BBB. In addition, taking advantage from the physiological up-regulation of low density lipoproteins receptor (LDLR) induced by statins as a consequence of the decreased cell cholesterol, we designed a liposomal-encapsulated doxorubicin, conjugated with a recombinant peptide containing the LDLR-binding site from human apoB-100. This nanoparticle is more uptaken by a LDLR-mediated endocytosis and less extruded by Pgp in drug-resistant solid tumors3, as well as in BBB cells pretreated with statins. Our work suggests a new combinatorial “Trojan horse” approach to increase anticancer drugs delivery across BBB.
Statins permeabilize blood-brain barrier to anticancer drugs
GHIGO, Dario Antonio;BOSIA, Amalia;RIGANTI, Chiara
2011-01-01
Abstract
Drug delivery across the blood-brain barrier (BBB) limits the efficacy of pharmacological therapy of brain tumors. For instance the anticancer drug doxorubicin, that is effective in vitro, has a poor efficacy in vivo because it is extruded through several efflux pumps like P-glycoprotein (Pgp), multidrug resistance-related proteins (MRPs) and breast cancer resistance protein (BCRP), present at high levels on BBB cells.1 We have previously observed that the anticholesterolemic drug statins reduce the activity of the efflux pumps in solid tumors with a nitric oxide (NO)-dependent mechanism.2 In this work we analyzed the effects of two lipohilic statins, mevastatin and simvastatin, on drug transport at BBB level. In primary human cerebral microvascular endothelial HCMEC/D3 cells, statins decrease the synthesis of cholesterol and isoprenoids, impair the activity of the small G-protein Rho and of the downstream effector RhoA kinase. By doing so, statins activate the IKK/NF-kB pathway, up-regulate the NO synthase isoform II and produce the nitration of critical tyrosine residues on Pgp and BCRP, decreasing the ATP-ase activity. As result, doxorubicin, a drug that is fully extruded by HCMEC/D3 cells, becomes able to cross the BBB. In addition, taking advantage from the physiological up-regulation of low density lipoproteins receptor (LDLR) induced by statins as a consequence of the decreased cell cholesterol, we designed a liposomal-encapsulated doxorubicin, conjugated with a recombinant peptide containing the LDLR-binding site from human apoB-100. This nanoparticle is more uptaken by a LDLR-mediated endocytosis and less extruded by Pgp in drug-resistant solid tumors3, as well as in BBB cells pretreated with statins. Our work suggests a new combinatorial “Trojan horse” approach to increase anticancer drugs delivery across BBB.
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