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.
↵ 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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