Inhibition of P-glycoprotein at the blood-brain barrier by phytochemicals derived from traditional Chinese medicine.

Publication type:
Journal article
Metadata:
Abstract
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.
Addresses
  • Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Heidelberg, Germany.
Autoren
  • 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
eISSN
1790-6245
Externe Identifier
  • PubMed Identifier: 20656985
Open access
false
ISSN
1109-6535
Ausgabe der Veröffentlichung
4
Zeitschrift
Cancer genomics & proteomics
Schlüsselwörter
  • Blood-Brain Barrier
  • Cells, Cultured
  • Animals
  • Swine
  • Drugs, Chinese Herbal
  • Cell Proliferation
  • Gene Expression Regulation
  • Molecular Structure
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
Sprache
eng
Medium
Print
Paginierung
191 - 205
Datum der Veröffentlichung
2010
Status
Published
Datum der Datenerfassung
2010
Titel
Inhibition of P-glycoprotein at the blood-brain barrier by phytochemicals derived from traditional Chinese medicine.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
7

Data source: Europe PubMed Central

Other metadata sources:
Abstract
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.
Autoren
  • 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
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/20656985
eISSN
1790-6245
Ausgabe der Veröffentlichung
4
Zeitschrift
Cancer Genomics Proteomics
Schlüsselwörter
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Animals
  • Blood-Brain Barrier
  • Cell Proliferation
  • Cells, Cultured
  • Drugs, Chinese Herbal
  • Gene Expression Regulation
  • Molecular Structure
  • Swine
Sprache
eng
Country
Greece
Paginierung
191 - 205
PII
7/4/191
Datum der Veröffentlichung
2010
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2010
Titel
Inhibition of P-glycoprotein at the blood-brain barrier by phytochemicals derived from traditional Chinese medicine.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
7

Data source: PubMed

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