Inhibition of P-glycoprotein at the blood-brain barrier by phytochemicals derived from traditional Chinese medicine.
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.
Mahringer
Anne
A
Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Heidelberg, Germany.
Karamustafa
Shirin
S
Klotz
Daniel
D
Kahl
Stefan
S
Konkimalla
V Badireenath
VB
Wang
Yifen
Y
Wang
Junsong
J
Liu
Hai-Yang
HY
Boechzelt
Herbert
H
Hao
Xiaojiang
X
Bauer
Rudolf
R
Fricker
Gert
G
Efferth
Thomas
T
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
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004365:Drugs, Chinese Herbal