Inhibition of P-glycoprotein at the Blood–Brain Barrier by Phytochemicals Derived from Traditional Chinese Medicine

Cancer Genomics - Proteomics

XIAOJIANG HAO¹  SHIRIN KARAMUSTAFA⁵  HAI-YANG LIU¹  HERBERT BOECHZELT²  RUDOLF BAUER⁴  ANNE MAHRINGER³  STEFAN KAHL⁴  YIFEN WANG¹  V. BADIREENATH KONKIMALLA⁵  THOMAS EFFERTH⁵  JUNSONG WANG¹  DANIEL KLOTZ⁵  GERT FRICKER³ 

[1] State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming, Institute of Botany, Chinese Academy of Sciences, Kunming, P.R. ChinaState Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming, Institute of Botany, Chinese Academy of Sciences, Kunming, P.R. ChinaState Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming, Institute of Botany, Chinese Academy of Sciences, Kunming, P.R. China;Joanneum Research, Graz, AustriaJoanneum Research, Graz, AustriaJoanneum Research, Graz, Austria;Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Heidelberg, GermanyInstitute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Heidelberg, GermanyInstitute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Heidelberg, Germany;Institute of Pharmaceutical Sciences, University of Graz, Graz, AustriaInstitute of Pharmaceutical Sciences, University of Graz, Graz, AustriaInstitute of Pharmaceutical Sciences, University of Graz, Graz, Austria;Pharmaceutical Biology (C015), German Cancer Research Center, Heidelberg, GermanyPharmaceutical Biology (C015), German Cancer Research Center, Heidelberg, GermanyPharmaceutical Biology (C015), German Cancer Research Center, Heidelberg, Germany

关键词: Bufadienolides;    calcein assay;    P-glycoprotein;    multidrug resistance;    natural products;    phytochemicals;    pharmacogenomics;   

DOI  :  

来源: Delinasios GJ CO

【 摘 要 】

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.

【 授权许可】

Unknown