Document Detail

Inhibition of P-glycoprotein at the blood-brain barrier by phytochemicals derived from traditional Chinese medicine.
MedLine Citation:
PMID:  20656985     Owner:  NLM     Status:  MEDLINE    
The blood-brain barrier (BBB) is a key determinant for drug transport through brain vessels. It restricts the pharmacological efficacy in numerous neurological diseases, including brain tumors. A major functional constituent of BBB is P-glycoprotein, which is also a major obstacle for effective chemotherapy of brain tumors. An appealing strategy is to selectively modulate BBB function using P-glycoprotein inhibitors. We assessed 57 chemically defined compounds derived from medicinal plants used in traditional Chinese medicine for their potential to inhibit P-glycoprotein. Nine phytochemicals inhibited P-glycoprotein in porcine brain capillary endothelial cells (PBCECs) and multidrug-resistant CEM/ADR5000 cells as shown by a calcein fluorescence assay. The cytotoxicity of the 57 phytochemicals was measured by a growth inhibition assay. Seven compounds inhibiting P-glycoprotein at lower doses were cytotoxic to drug-sensitive parental CCRF-CEM cells at higher doses. Of them, five were not cross-resistant to CEM/ADR5000 cells (baicalein, bufalin, glybomine B, deoxyserofendic acid, and shogaol). Bufalin was chosen as a lead compound. Of a further six bufalin-related compounds, scillarenin showed improved features in comparison to bufalin. It was cytotoxic to cancer cells at a nanomolar range. COMPARE and hierarchical cluster analyses of microarray-based mRNA expression were used to investigate determinants of sensitivity or resistance of the bufalin-related compounds downstream of P-glycoprotein. CEM/ADR5000 cells were not cross-resistant, but were collaterally sensitive towards scillarenin. Finally, scillarenin inhibited P-glycoprotein in PBCECs. Taken together, these data show that scillarenin is a potential novel candidate for P-glycoprotein inhibition at BBB, and, thereby, may improve the efficacy of therapy regimens in treating brain diseases.
Anne Mahringer; Shirin Karamustafa; Daniel Klotz; Stefan Kahl; V Badireenath Konkimalla; Yifen Wang; Junsong Wang; Hai-Yang Liu; Herbert Boechzelt; Xiaojiang Hao; Rudolf Bauer; Gert Fricker; Thomas Efferth
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Cancer genomics & proteomics     Volume:  7     ISSN:  1790-6245     ISO Abbreviation:  Cancer Genomics Proteomics     Publication Date:    2010 Jul-Aug
Date Detail:
Created Date:  2010-07-26     Completed Date:  2010-09-23     Revised Date:  2012-01-18    
Medline Journal Info:
Nlm Unique ID:  101188791     Medline TA:  Cancer Genomics Proteomics     Country:  Greece    
Other Details:
Languages:  eng     Pagination:  191-205     Citation Subset:  IM    
Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Heidelberg, Germany.
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MeSH Terms
Blood-Brain Barrier*
Cell Proliferation / drug effects
Cells, Cultured
Drugs, Chinese Herbal / chemistry,  pharmacology*
Gene Expression Regulation / drug effects
Molecular Structure
P-Glycoprotein / antagonists & inhibitors*,  metabolism
Reg. No./Substance:
0/Drugs, Chinese Herbal; 0/P-Glycoprotein

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