Inhibition of P‐glycoprotein function by procyanidine on blood–brain barrier

Abstract

The inhibitory effects of procyanidine, one of the components from the bark of Pinus massoniana Lamb, on the P-glycoprotein (P-gp) function of the blood-brain barrier (BBB) were studied using in vitro rat brain microvessel endothelial cells (RBMECs) and nude mice transplanted with human cerebroma. Quantitative accumulation and efflux of rhodamine 123 (Rh123), a P-gp substrate, were determined using a fluorescence spectrophotometer as a measure of P-gp function. Procyanidine markedly increased the accumulation of Rh123 by inhibiting its efflux in a dose-dependent manner. A 5-fold increase in cellular Rh123 was observed for procyanidine at 10 micromol/L. The verapamil-stimulated ATPase activity in plasma membrane vesicles from the RBMECs was estimated by measuring inorganic phosphate liberation. Procyanidine significantly inhibited the verapamil-induced P-gp ATPase activity by 78% when pretreated with 10 micromol/L in a concentration-dependent manner. The inhibition of P-gp by procyanidine was suggested to be at least partly due to its inhibition of P-gp ATPase. Procyanidine markedly improved the therapeutic effects of adriamycin (ADM) on nude mice transplanted with human cerebroma, compared with solitary treatment of ADM. The combination of 80 mg/kg procyanidine with 2 mg/kg ADM significantly elevated the days of survival with an increase in life span of 76%. The findings suggested that procyanidine was a potent inhibitor of P-gp on BBB and could improve the therapeutic effects on cerebral tumors of some drugs which are difficult to accumulate in the brain.

Grape Seed Procyanidin Reversal of P-glycoprotein Associated Multi-Drug Resistance via Down-regulation of NF-κB and MAPK/ERK Mediated YB-1 Activity in A2780/T Cells

“…In these studies, GSP is found to reverse the MDR effect in blood-brain barrier by blocking the function of P-gp [30] but the MDR reversal effect of GSP in chemotherapeutic agent resistant cancer cells and even the mechanism of MDR reversal is not clear. Additionally, there's no report on the influence of P-gp expression by GSP, and also the mechanism is unknown.…”

“…Recent years, GSP is most widely studied in terms of their bioactivities. It's found that GSP could inhibit the function of P-gp on blood-brain barrier [30]. But the role of GSP in reversing cancer cells MDR by inhibiting P-gp expression as well as the mechanism remains unreported.…”

P-glycoprotein inhibitors of natural origin as potential tumor chemo-sensitizers: A review

“…1 ) markedly increased the accumulation of Rh123 (rhodamine 123) within cells by inhibiting its efflux in a dose-dependent manner. Procyanidine was a potent inhibitor of P-gp on BBB (blood brain barrier) and could improve the therapeutic effects on cerebral tumors of some drugs which are difficult to accumulate in the brain [71] .…”

In Vitro Studies of Anti-Hemolytic and Cytotoxic Activity of Procyanidin-Rich Extract from the Leaves of Actinidia arguta

“…The reversal of MDR in cancer cells can be improved by the application of chemotherapy in combination with resistance modifi ers [Szabo & Molnar, 1998;Szabo et al, 2000]. Great numbers of natural plant compounds, including procyanidins and kiwi fruit extract, have been shown to block the P-glycoprotein activity [He et al, 2009;Motohashi et al, 2002]. It was found that grape procyanidins reversed the MDR effect in blood-brain barrier by blocking the function of P-gp [He et al, 2009] and strongly inhibited P-gp expression by blocking MDR1 gene transcription.…”

“…Great numbers of natural plant compounds, including procyanidins and kiwi fruit extract, have been shown to block the P-glycoprotein activity [He et al, 2009;Motohashi et al, 2002]. It was found that grape procyanidins reversed the MDR effect in blood-brain barrier by blocking the function of P-gp [He et al, 2009] and strongly inhibited P-gp expression by blocking MDR1 gene transcription. They also increased the intracellular accumulation of the P-gp substrate rhodamine-123 in A2780/T cells [Zhao et al, 2013].…”