title: 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.
authors: Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
authors: Bo-xin
authors: BX
authors: Zhao
authors: Ya-bin
authors: YB
authors: Sun
authors: Sheng-qi
authors: SQ
authors: Wang
authors: Lian
authors: L
authors: Duan
authors: Qi-lu
authors: QL
authors: Huo
authors: Fei
authors: F
authors: Ren
authors: Guo-feng
authors: GF
authors: Li
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D044946:Biflavonoids / Q000494:pharmacology*; D002392:Catechin / Q000494:pharmacology*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology / Q000633:toxicity; D018432:Drug Resistance, Multiple; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology / Q000633:toxicity; D044945:Proanthocyanidins / Q000494:pharmacology*; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020112:Rhodamine 123 / Q000378:metabolism; D012639:Seeds / Q000737:chemistry; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D027843:Vitis / Q000737:chemistry; D051840:Y-Box-Binding Protein 1 / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D044946:Biflavonoids; D016328:NF-kappa B; D044945:Proanthocyanidins; D012333:RNA, Messenger; D051840:Y-Box-Binding Protein 1; D020112:Rhodamine 123; C017674:procyanidin; D004317:Doxorubicin; D002392:Catechin; D020929:Mitogen-Activated Protein Kinase Kinases; D017239:Paclitaxel
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