Coencapsulation of disulfiram and doxorubicin in liposomes strongly reverses multidrug resistance in breast cancer cells

International Journal of Pharmaceutics
Francesca RolleSilvia Arpicco

Abstract

Disulfiram (DSF) is an inhibitor of P-glycoprotein (Pgp), the main obstacle limiting the success of doxorubicin (DOX), but it has poor solubility and stability. With the aim to overcome these limitations we prepared liposomes coencapsulating DSF and DOX (LipoDSF-DOX). Liposome stability, drugs release profile, effects on DOX cytotoxicity, Pgp activity and expression in breast cancer cells were evaluated. We observed that LipoDSF-DOX with a 1:3 weight ratio, with DSF in lipid bilayer and DOX in aqueous core, released DSF faster than DOX. LipoDSF-DOX increased DOX intracellular accumulation and cytotoxicity in Pgp-expressing breast cancer cells, with an efficacy superior to the mixture of free DSF and DOX, thanks to a differential kinetics of release of DSF and DOX when carried by liposomes. The mechanism of the increased DOX retention relied on the DSF-induced sulfhydraton of Pgp and followed by its ubiquitination. These events reduced Pgp expression and catalytic activity in LipoDSF-DOX-treated cells. Our results show that LipoDSF-DOX effectively reversed DOX resistance in Pgp-expressing breast cancer cells, exploiting the temporally different kinetics of release of DSF and DOX, optimized to decrease expression and activity of ...Continue Reading

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Citations

Dec 30, 2020·Biomedit︠s︡inskai︠a︡ khimii︠a︡·L V KostryukovaE G Tikhonova
Aug 24, 2020·Biochimica Et Biophysica Acta. Molecular Cell Research·Francesca MasettoMassimo Donadelli
Dec 5, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Bethany AlmeidaJames B Delehanty
Jul 17, 2021·European Journal of Pharmacology·Sepideh MirzaeiSaeed Samarghandian

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