title: Zuo Jin Wan reverses P-gp-mediated drug-resistance by inhibiting activation of the PI3K/Akt/NF-κB pathway.
abstract: BACKGROUND
  Zuo-Jin-Wan (ZJW), a traditional Chinese medicine formula, has been identified to be effective against drug resistance in cancer. In the present study, we investigated the effect of ZJW on acquired oxaliplatin-resistant and the PI3K/Akt/NF-κB pathway in vitro.
  
  
  METHODS
  We tested the dose-response relationship of ZJW on reversing drug-resistance by CCK-8 assay and flow cytometry analysis in vitro. The protein expression of P-gp, MRP-2, LRP, and ABCB1 mRNA expression level were evaluated by Western blot and quantitative RT-PCR. The activities of PI3K/Akt/NF-κB pathway were also examined with or without ZJW, including Akt, IκB, p65 and their phosphorylation expression.
  
  
  RESULTS
  We found that ZJW significantly enhanced the sensitivity of chemotherapeutic drugs and increased oxaliplatin (L-OHP)-induced cell apoptosis in a time- and dose-dependent manner. Moreover, both ZJW and a PI3K specific inhibitor (LY294002) suppressed phosphorylation of Akt (Ser473) and NF-κB, which is necessary in the activation of the PI3K/Akt/NF-κB pathway. The effect of ZJW in reversing drug-resistance and suppressing phosphorylation of Akt (Ser473) and NF-κB were weakened after treatment with a PI3K/Akt activator in HCT116/L-OHP cells.
  
  
  CONCLUSIONS
  Our study has provided the first direct evidence that ZJW reverses drug-resistance in human colorectal cancer by blocking the PI3K/Akt/NF-κB signaling pathway, and could be considered as a useful drug for cancer therapy.
authors.forename: Hua
authors.initials: H
authors.lastname: Sui
authors.forename: Shu-Fang
authors.initials: SF
authors.lastname: Pan
authors.forename: Yu
authors.initials: Y
authors.lastname: Feng
authors.forename: Bao-Hui
authors.initials: BH
authors.lastname: Jin
authors.forename: Xuan
authors.initials: X
authors.lastname: Liu
authors.forename: Li-Hong
authors.initials: LH
authors.lastname: Zhou
authors.forename: Feng-Gang
authors.initials: FG
authors.lastname: Hou
authors.forename: Wen-Hai
authors.initials: WH
authors.lastname: Wang
authors.forename: Xiao-Ling
authors.initials: XL
authors.lastname: Fu
authors.forename: Zhi-Fen
authors.initials: ZF
authors.lastname: Han
authors.forename: Jian-Lin
authors.initials: JL
authors.lastname: Ren
authors.forename: Xiao-Lan
authors.initials: XL
authors.lastname: Shi
authors.forename: Hui-Rong
authors.initials: HR
authors.lastname: Zhu
authors.affiliation: Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Lzwf@hotmail.com.
authors.forename: Qi
authors.initials: Q
authors.lastname: Li
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D006801:Humans; D000089762:Multidrug Resistance-Associated Protein 2; D016328:NF-kappa B / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D004365:Drugs, Chinese Herbal; D000089762:Multidrug Resistance-Associated Protein 2; D016328:NF-kappa B; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C000715087:ABCC2 protein, human; C560510:Zuo-Jin-Wan
references.citation: Eur J Pharm Sci. 2000 Oct;11(4):265-83
references.pmid: 11033070
references.citation: Planta Med. 2009 Sep;75(11):1215-20
references.pmid: 19350478
references.citation: J Int Med Res. 2012;40(2):426-35
references.pmid: 22613403
references.citation: J Clin Oncol. 2010 Feb 20;28(6):1075-83
references.pmid: 20085938
references.citation: BMC Complement Altern Med. 2014 Jul 14;14:241
references.pmid: 25023038
references.citation: Cancer Lett. 2014 Jun 1;347(2):159-66
references.pmid: 24657660
references.citation: Int J Biol Sci. 2012;8(1):1-14
references.pmid: 22211100
references.citation: Chin J Integr Med. 2014 Aug;20(8):610-7
references.pmid: 23543356
references.citation: Nature. 1999 Sep 2;401(6748):82-5
references.pmid: 10485710
references.citation: Methods Mol Biol. 2004;261:337-50
references.pmid: 15064468
references.citation: Oncogene. 2003 Nov 6;22(50):8137-44
references.pmid: 14603254
references.citation: Mol Nutr Food Res. 2010 Jul;54(7):918-28
references.pmid: 20077420
references.citation: Eur J Neurosci. 2004 Jun;19(12):3375-81
references.pmid: 15217394
references.citation: Oncogene. 2002 Mar 27;21(13):1945-54
references.pmid: 11960367
references.citation: Arch Pharm Res. 2006 Sep;29(9):757-61
references.pmid: 17024849
references.citation: Evid Based Complement Alternat Med. 2013;2013:957078
references.pmid: 23533531
references.citation: Cytokine. 2011 Nov;56(2):365-75
references.pmid: 21742513
references.citation: Clin Cancer Res. 2011 Apr 1;17(7):1839-49
references.pmid: 21325072
references.citation: Curr Opin Genet Dev. 2010 Feb;20(1):87-90
references.pmid: 20006486
references.citation: J Integr Med. 2014 Mar;12(2):76-85
references.pmid: 24666673
references.citation: Neoplasma. 2012;59(3):248-56
references.pmid: 22329846
references.citation: PLoS One. 2013 Jul 15;8(7):e69240
references.pmid: 23869238
references.citation: J Integr Med. 2014 Mar;12(2):67-75
references.pmid: 24666672
references.citation: Oncogene. 2003 Jan 9;22(1):90-7
references.pmid: 12527911
references.citation: BMC Complement Altern Med. 2013 Sep 17;13:227
references.pmid: 24041039
references.citation: Free Radic Res. 2007 Oct;41(10):1099-108
references.pmid: 17886031
references.citation: Chin Med. 2012 Apr 30;7(1):11
references.pmid: 22546215