| Inhibition of P-glycoprotein at the blood-brain barrier by phytochemicals derived from traditional Chinese medicine. | |
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MedLine Citation:
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PMID: 20656985 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article |
Journal Detail:
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Title: Cancer genomics & proteomics Volume: 7 ISSN: 1790-6245 ISO Abbreviation: Cancer Genomics Proteomics Publication Date: 2010 Jul-Aug |
Date Detail:
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Created Date: 2010-07-26 Completed Date: 2010-09-23 Revised Date: 2012-01-18 |
Medline Journal Info:
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Nlm Unique ID: 101188791 Medline TA: Cancer Genomics Proteomics Country: Greece |
Other Details:
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Languages: eng Pagination: 191-205 Citation Subset: IM |
Affiliation:
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Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Heidelberg, Germany. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals 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 Swine |
| Chemical | |
Reg. No./Substance:
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0/Drugs, Chinese Herbal; 0/P-Glycoprotein |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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