title: Inhibition of P-glycoprotein at the blood-brain barrier by phytochemicals derived from traditional Chinese medicine.
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.
authors.affiliation: Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Mahringer
authors.forename: Shirin
authors.initials: S
authors.lastname: Karamustafa
authors.forename: Daniel
authors.initials: D
authors.lastname: Klotz
authors.forename: Stefan
authors.initials: S
authors.lastname: Kahl
authors.forename: V Badireenath
authors.initials: VB
authors.lastname: Konkimalla
authors.forename: Yifen
authors.initials: Y
authors.lastname: Wang
authors.forename: Junsong
authors.initials: J
authors.lastname: Wang
authors.forename: Hai-Yang
authors.initials: HY
authors.lastname: Liu
authors.forename: Herbert
authors.initials: H
authors.lastname: Boechzelt
authors.forename: Xiaojiang
authors.initials: X
authors.lastname: Hao
authors.forename: Rudolf
authors.initials: R
authors.lastname: Bauer
authors.forename: Gert
authors.initials: G
authors.lastname: Fricker
authors.forename: Thomas
authors.initials: T
authors.lastname: Efferth
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D015394:Molecular Structure; D013552:Swine
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004365:Drugs, Chinese Herbal