RT Journal Article
SR Electronic
T1 Key Role of Nuclear Factor-κB in the Cellular Pharmacokinetics of Adriamycin in MCF-7/Adr Cells: The Potential Mechanism for Synergy with 20(<em>S</em>)-Ginsenoside Rh2
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1900
OP 1908
DO 10.1124/dmd.112.045187
VO 40
IS 10
A1 Jingwei Zhang
A1 Meng Lu
A1 Fang Zhou
A1 Haopeng Sun
A1 Gang Hao
A1 Xiaolan Wu
A1 Guangji Wang
YR 2012
UL http://dmd.aspetjournals.org/content/40/10/1900.abstract
AB 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.