Six Phthalides as Potent Modulators of the Blood Tumor Barrier Increase the Transmembrane Transport of Compatible Compounds Via Transcellular and Paracellular Pathways

Abstract

The treatment of brain tumors is greatly limited due to the presence of the blood tumor barrier (BTB). Our previous research has shown that the essential oil of chuanxiong promoted temozolomide entry into glioma cells and enhanced temozolomide-induced anticancer efficiency in vivo. Phthalides account for the largest proportion of essential oil and, therefore, this study was conducted to investigate the effects of six phthalides on the transmembrane transport of compatible compounds across the BTB and the mechanism. The results showed that different concentrations of senkyunolide H (SH), senkyunolide A (SA), ligustilide (LIG), butylidenephthalide (BP), n-butylphthalide (NBP) and neocnidilide (NOL) significantly increase the permeability from A (apical side) to B (basolateral side) (Papp_(AB)) of fluorescein isothiocyanate 4000 (FITC4000), while NBP, NOL and SA could also significantly increase Papp_(B→A). Western blot analysis indicated that these phthalides down-regulated expressions of claudin-5, occludin and ZO-1 to increase the permeability of BTB. LIG, SA, SH, NBP and NOL significantly increased Papp_(AB) and the efflux ratio of the P-gp substrate rhodamine 123 attribute to down-regulate the expressions of P-gp. The expression of caveolin-1 was also down-regulated by the six phthalides. LIG, SA, SH, NBP and NOL acted as effective absorption enhancers in BTB via both the transcellular route and the paracellular route.