Entinostat reverses P-glycoprotein activation in snail-overexpressing adenocarcinoma HCC827 cells.

Entinostat reverses P-glycoprotein activation in snail-overexpressing adenocarcinoma HCC827 cells.

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Epithelial-to-mesenchymal transition (EMT) in cancer cells facilitates tumor progression by promoting invasion and metastasis.Snail is a transcriptional factor that induces EMT, while P-glycoprotein (P-gp) is an efflux transporter involved in anticancer drug resistance, and P-gp efflux activity is stimulated in Snail-overexpressing lung cancer cells CAYENNE 42 with EMT characteristics.Since the histone deacetylase (HDAC) inhibitor entinostat (Ent) reverses EMT features, our aim in this study was to determine whether Ent also suppresses P-gp activation in Snail-induced cells.First, we confirmed that Ent treatment reduced migration activity, downregulated E-cadherin and upregulated vimentin at the mRNA level in Snail-overexpressing cells, thus inhibiting EMT.Efflux and uptake assays using rhodamine123 (Rho123), a fluorescent P-gp substrate, showed that Ent also inhibited Snail-induced activation of Breakfast P-gp.

Moreover, P-gp activity was more strongly inhibited by Ent in Snail-overexpressing cells than in Mock cells.When we evaluated the uptakes of Rho123 by LLC-PK1 cells and P-gp-overexpressing LLC-GA5COL150 cells, Rho123 accumulation in LLC-GA5COL150 cells was significantly decreased compared with that in LLC-PK1 cells.Coincubation with Ent had no effect on Rho123 accumulation in either of the cell lines.Thus, Ent appears to be an inhibitor, but not a substrate, of P-gp at low concentration.Our results suggest that Ent treatment might suppress not only Snail-induced cancer malignant alteration, but also P-gp-mediated multidrug resistance.