Planta Med 2007; 73(3): 212-220
DOI: 10.1055/s-2007-967120
Original Paper
Pharmacology
© Georg Thieme Verlag KG Stuttgart · New York

Schisandrol A from Schisandra chinensis Reverses P-Glycoprotein-Mediated Multidrug Resistance by Affecting Pgp-Substrate Complexes

Wang-Fun Fong1 , Chi-Keung Wan2 , Guo-Yuan Zhu2 , Apurba Chattopadhyay3 , Saibal Dey3 , 4 , Zhongzhen Zhao1 , Xiao-Ling Shen2
  • 1School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, P. R. China
  • 2Bioactive Products Research Group, Department of Biology and Chemistry, City University of Hong Kong, Hong Kong SAR, P. R. China
  • 3Department of Biochemistry and Molecular Biology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA
  • 4A portion of the work was funded by United States Public Health Services Grant GM067926 to Saibal Dey
Further Information

Publication History

Received: October 27, 2006

Accepted: January 21, 2007

Publication Date:
22 February 2007 (online)

Abstract

Recent studies have shown that dibenzocyclooctadiene lignans may reverse P-glycoprotein-mediated multidrug resistance (Pgp-MDR) in cancer cells; however, the mechanism of action remains unknown. Through screening of herbs, we found that schisandrol A (SCH) isolated from Fructus Schisandrae (the dried fruit of Schisandra chinensis (Turcz.) Baill.) sensitized Pgp-MDR HepG2-DR cells by interfering with the function of Pgp-substrate complexes. In Pgp-MDR cells, SCH enhanced the cytotoxicity of cancer drugs that are Pgp substrates and restored vinblastine-induced G2/M arrest without lowering Pgp expression. SCH increased cellular retention of Pgp substrates such as rhodamine 123. In Pgp-overexpressing membrane preparations, SCH stimulated basal Pgp-ATPase thus showing some substrate-like function. However, SCH was not a competitive inhibitor for verapamil or progesterone and decreased their Km. In the presence of substrates, SCH decreased the reactivity between Pgp and the monoclonal antibody UIC-2 which is normally increased with active substrate-Pgp complexes. The labeling of active Pgp transport sites by [125I]-iodoarylazidoprazosin was partially blocked by SCH. SCH did not affect the activity of the mutant Pgp F983A suggesting that SCH acted differently than the thioxanthene type of Pgp allosteric inhibitors. Our results suggest that SCH acts by affecting the normal formation and functioning of the Pgp-substrate complexes.

Abbreviations

[125I]IAAP:[125I]-iodoarylazidoprazosin

MDR:multidrug resistance

Pgp:P-glycoprotein

PI:propidium iodide

Rh-123:rhodamine 123

SCH:schisandrol A

SRB:sulforhodamine B

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Prof. W.-F. Fong

School of Chinese Medicine

Hong Kong Baptist University

Hong Kong SAR

People’s Republic of China

Phone: +852-3411-2928

Fax: +852-3411-2902.

Email: wffong@hkbu.edu.hk

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