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.
Highlights
Plenty of cancer cells develop resistance against their chemotherapeutic agents which are structurally and mechanistically various
Paclitaxel and adriamycin, are widely used in ovarian cancer chemotherapy treatment, come out unsatisfactory only because the tumor lost the sensibility to the chemotherapeutic agents [1], which currently known as multi-drug resistance (MDR)
We demonstrated whether the MDR1 expression inhibited by Grape seed procyanidin (GSP) has involved inhibitory effect of nuclear factor k-light-chain-enhancer of activated B cells (NF-kB) activity and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway mediated Y-box binding protein 1 (YB-1) in A2780/T cells
Summary
Plenty of cancer cells develop resistance against their chemotherapeutic agents which are structurally and mechanistically various. Paclitaxel and adriamycin, are widely used in ovarian cancer chemotherapy treatment, come out unsatisfactory only because the tumor lost the sensibility to the chemotherapeutic agents [1], which currently known as multi-drug resistance (MDR). Intrinsic and acquired MDR mainly results from the overexpression of cell membrane-bound ATP-binding cassette (ABC) transporters, which actively extrude a variety of chemotherapeutic drugs out of the cancer cells [2]. Pglycoprotein (p-gp), encoded by MDR1 gene, is able to transport a wide range of anticancer agents such as the anthracyclines, vinca alkaloids, taxanes, and epipodophyllotoxins [3], thereby may be responsible for intrinsic and acquired drug resistance in numerous human cancers. Suppression of P-gp function and expression may certain reverse the P-gp associated MDR in cancer cells that comes to increase the efficacy of chemotherapy
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