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

PLOS ONE, Dec 2019

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.

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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

et al. (2013) Grape Seed Procyanidin Reversal of P-glycoprotein Associated Multi-Drug Resistance via Down-regulation of NF-kB and MAPK/ERK Mediated YB-1 Activity in A2780/T Cells. PLoS ONE 8(8): e71071. doi:10.1371/journal.pone.0071071 Grape Seed Procyanidin Reversal of P-glycoprotein Associated Multi-Drug Resistance via Down-regulation of NF-kB and MAPK/ERK Mediated YB-1 Activity in A2780/T Cells Bo-xin Zhao 0 Ya-bin Sun 0 Sheng-qi Wang 0 Lian Duan 0 Qi-lu Huo 0 Fei Ren 0 Guo-feng Li 0 Deyu Fang, Northwestern University Feinberg School of Medicine, United States of America 0 1 Department of Pharmacy, Nanfang Hospital, Southern Medical University , Guangzhou, Guangdong, China, 2 GCP Office , Nanfang Hospital, Southern Medical University , Guangzhou, Guangdong , China 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-kB(NF-kB) activity, IkB degradation level and NF-kB/p65 nuclear translocation induced by lipopolysaccharide (LPS) and receptor activator for nuclear factor-kB 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-kB and MAPK/ERK pathway induced by LPS was attenuated by GSP administration. Compared with PDTC and U1026, inhibitor of NF-kB and MAPK/ERK respectively, GSP showed the same tendency of down-regulating NF-kB and MAPK/ERK mediated YB1 activities. Thus, GSP reverses P-gp associated MDR by inhibiting the function and expression of P-gp through downregulation of NF-kB 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. - Funding: This work was supported by the Grants from NSFC (No. 81073061), Science and Technology Planning Project of Guangdong Province (No. 2010B0370700014) and the Presidential Foundation of Nanfang Hospital (No. 2012B012 and 2012C028). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. . These authors contributed equally to this work. Plenty of cancer cells develop resistance against their chemotherapeutic agents which are structurally and mechanistically various. For example, 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]. Importantly, 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. Recently, P-gp associated MDR is proved to be effectively overcome by either blocking its drug-pump function or inhibiting its expression [4]. Thus, 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. Since P-gp associated MDR was first identified exceed semicentury ago, researches on new effective P-gp inhibitors have attracted extensive attention worldwide. The discovery of verapamil reversal MDR by blocking P-gp in 1980 s led to a wave of Pgp inhibitor development, various agents including designed compounds have been reported to suppress P-gp [5,6]. However, most of these agents necessitated high doses which caused serious side-effects and the intrinsic cytotoxicity, especially the designed compounds, by dose-limiting toxicity, consequently, relevan (...truncated)


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Bo-xin Zhao, Ya-bin Sun, Sheng-qi Wang, Lian Duan, Qi-lu Huo, Fei Ren, Guo-feng Li. 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, PLOS ONE, 2013, 8, DOI: 10.1371/journal.pone.0071071