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Research ArticleArticle

Key Role of Nuclear Factor-κB in the Cellular Pharmacokinetics of Adriamycin in MCF-7/Adr Cells: The Potential Mechanism for Synergy with 20(S)-Ginsenoside Rh2

Jingwei Zhang, Meng Lu, Fang Zhou, Haopeng Sun, Gang Hao, Xiaolan Wu and Guangji Wang
Drug Metabolism and Disposition October 2012, 40 (10) 1900-1908; DOI: https://doi.org/10.1124/dmd.112.045187
Jingwei Zhang
Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu, China (J.Z., M.L., F.Z., G.H., X.W., G.W.); and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, Jiangsu, China (H.S.)
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Meng Lu
Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu, China (J.Z., M.L., F.Z., G.H., X.W., G.W.); and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, Jiangsu, China (H.S.)
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Fang Zhou
Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu, China (J.Z., M.L., F.Z., G.H., X.W., G.W.); and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, Jiangsu, China (H.S.)
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Haopeng Sun
Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu, China (J.Z., M.L., F.Z., G.H., X.W., G.W.); and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, Jiangsu, China (H.S.)
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Gang Hao
Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu, China (J.Z., M.L., F.Z., G.H., X.W., G.W.); and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, Jiangsu, China (H.S.)
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Xiaolan Wu
Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu, China (J.Z., M.L., F.Z., G.H., X.W., G.W.); and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, Jiangsu, China (H.S.)
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Guangji Wang
Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu, China (J.Z., M.L., F.Z., G.H., X.W., G.W.); and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, Jiangsu, China (H.S.)
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Abstract

We have previously demonstrated that ginsenoside 20(S)-Rh2 is a potent ATP-binding cassette (ABC) B1 inhibitor and explored the cellular pharmacokinetic mechanisms for its synergistic effect on the cytotoxicity of Adriamycin. The present studies were conducted to elucidate the key factors that influenced ABCB1 expression, which could further alter Adriamycin cellular pharmacokinetics. Meanwhile, the influence of 20(S)-Rh2 on the above factors was revealed for explaining its synergistic effect from the view of ABCB1 expression. The results indicated that 20(S)-Rh2 inhibited Adriamycin-induced ABCB1 expression in MCF-7/Adr cells. Subsequent analyses indicated that 20(S)-Rh2 markedly inhibited Adriamycin-induced activation of the mitogen-activated protein kinase (MAPK)/nuclear factor (NF)-κB pathway, NF-κB translocation to the nucleus, and NF-κB binding activity. Furthermore, 20(S)-Rh2 repressed the Adriamycin-enhanced ability of NF-κB to bind to the human multidrug resistance (MDR1) promoter, and MAPK/NF-κB inhibitors and NF-κB small interfering RNA reversed the Adriamycin-induced expression of ABCB1. Moreover, the cellular pharmacokinetics of Adriamycin was also significantly altered by inhibiting NF-κB. In conclusion, the MAPK/NF-κB pathway mediates Adriamycin-induced ABCB1 expression and subsequently alters the cellular pharmacokinetics of Adriamycin. It was speculated that 20(S)-Rh2 acted on this pathway to lower Adriamycin-induced ABCB1 expression in MCF-7/Adr cells, which provided mechanism-based support to the development of 20(S)-Rh2 as a MDR reversal agent.

Footnotes

  • This work was supported by China National Nature Science Foundation [Grant 30973583]; China “Creation of New Drugs” Key Technology Projects [Grants 2009ZX09304-001, 2009ZX09502-004]; Jiangsu Province Nature Science Foundation [Grants BE2010723, BK2010437]; and Fundamental Research Funds for the Central Universities [Grants JKY2011072, JKZ2011008].

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    http://dx.doi.org/10.1124/dmd.112.045187.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    ABC
    ATP-binding cassette
    MDR
    multidrug resistance
    NF-κB
    nuclear factor κB
    MAPK
    mitogen-activated protein kinase
    SB203580
    4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole
    U0126
    1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene
    SP6001125
    anthra[1–9-cd]pyrazol-6(2H)-one
    PD98059
    2′-amino-3′-methoxyflavone
    BAY 11-7082
    3-[(4-methylphenyl)sulfonyl]-(2E)-propenenitrile
    p
    phospho
    ERK
    extracellular signal-regulated kinase
    JNK
    c-Jun NH2-terminal kinase
    IκB
    inhibitor of nuclear factor-κB
    IKK
    IκB kinase complex
    siRNA
    small interfering RNA
    EMSA
    electrophoretic mobility shift
    ChIP
    chromatin immunoprecipitation
    Q
    quantitative
    PCR
    polymerase chain reaction.

  • Received February 20, 2012.
  • Accepted June 27, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (10)
Drug Metabolism and Disposition
Vol. 40, Issue 10
1 Oct 2012
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Research ArticleArticle

NF-κB REGULATES CELLULAR PHARMACOKINETICS OF ADRIAMYCIN

Jingwei Zhang, Meng Lu, Fang Zhou, Haopeng Sun, Gang Hao, Xiaolan Wu and Guangji Wang
Drug Metabolism and Disposition October 1, 2012, 40 (10) 1900-1908; DOI: https://doi.org/10.1124/dmd.112.045187

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Research ArticleArticle

NF-κB REGULATES CELLULAR PHARMACOKINETICS OF ADRIAMYCIN

Jingwei Zhang, Meng Lu, Fang Zhou, Haopeng Sun, Gang Hao, Xiaolan Wu and Guangji Wang
Drug Metabolism and Disposition October 1, 2012, 40 (10) 1900-1908; DOI: https://doi.org/10.1124/dmd.112.045187
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