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

Abstract

The expression and function of P-glycoprotein (P-gp) is associated with the phenotype of multi-drug resistance (MDR), leading chemotherapy failure of patients suffered with cancer. Grape seed procyanidin(GSP) is a natural polyphenol supplement with anti-inflammatory effect. Present study assessed a new use of GSP on the MDR reversal activity and its possible molecular mechanisms in MDR1-overpressing paclitaxel resistant ovarian cancer cells. Our results showed GSP significantly enhanced the cytotoxicity of paclitaxel and adriamycin in paclitaxel resistant A2780/T cells but its parental A2780 cells. Furthermore, GSP strongly inhibited P-gp expression by blocking MDR1 gene transcription, as well as, increased the intracellular accumulation of the P-gp substrate rhodamine-123 in A2780/T cells. Nuclear factor-κB(NF-κB) activity, IκB degradation level and NF-κB/p65 nuclear translocation induced by lipopolysaccharide (LPS) and receptor activator for nuclear factor-κB ligand (RANKL) were markedly inhibited by pre-treatment with GSP. Meanwhile, GSP inhibited MAPK/ERK pathway by decreasing the phosphorylation of ERK1/2, resulting in reduced the Y-box binding protein 1 (YB-1) activation with blocking its nuclear translocation. Moreover, the up-regulation of P-gp expression, the activation of AKT/NF-κB and MAPK/ERK pathway induced by LPS was attenuated by GSP administration. Compared with PDTC and U1026, inhibitor of NF-κB and MAPK/ERK respectively, GSP showed the same tendency of down-regulating NF-κB and MAPK/ERK mediated YB-1 activities. Thus, GSP reverses P-gp associated MDR by inhibiting the function and expression of P-gp through down-regulation of NF-κB activity and MAPK/ERK pathway mediated YB-1 nuclear translocation, offering insight into the mechanism of reversing MDR by natural polyphenol supplement compounds. GSP could be a new potential MDR reversal agent used for combination therapy with chemotherapeutics in clinic.

Effect of shikonin on multidrug resistance in HepG2: The role of SIRT1

“…The function and expression of MDR1/P-gp are regulated by several mechanisms. Recently, researchers found that the function and expression of P-gp are regulated by NF-kB activity and MAPK/ERK pathway-mediated Y-box binding protein 1 nuclear translocation (Zhao et al, 2013). In breast tumor cells, the expression and chemoresistance of MDR1 gene are mediated by SIRT1 regulating beta-catenin signaling and NF-kB-specific transcriptional activity (Bourguignon et al, 2009).…”

Enhancing Activity of Anticancer Drugs in Multidrug Resistant Tumors by Modulating P-Glycoprotein through Dietary Nutraceuticals

“…This effect was found to be associated with p-gp inhibition. Further mechanistic study revealed that GSP reversed MDR by inhibiting the function and expression of p-gp via inhibition of NF-КB and YB-1 translocation into nucleus through dephosphorylation of AKT and ERK1/2 respectively (Zhao et al, 2013).…”

Molecular mechanisms of drug resistance and its reversal in cancer

“…Recently, secondary metabolites such as phenolics, terpenoids and alkaloids were found to be potential Pgp inhibitors in colon and leukemia cells (Eid et al, 2013). In paclitaxel-resistant ovarian cancer cells with Pgp overexpression, a natural polyphenol was shown to overcome resistance by inhibiting the expression and function of Pgp through down-regulation of NF-kB activity and MAPK/ERK pathway (Zhao et al, 2013).…”