Inhibition of P-glycoprotein by two artemisinin derivatives  

作　　者：Babette STEGLICH Anne MAHRINGER Ying LI Gary H.POSNER Gert FRICKER Thomas EFFERTH 

机构地区：[1]Department of Pharmaceutical Biology,Institute of Pharmacy and Biochemistry,Johannes Gutenberg University,Staudinger Weg 5,551 Mainz,Germany [2]Institute of Pharmacy and Molecular Biotechnology,Karl Ruprecht University,Heidelberg,Germany [3]Department of Synthetic Chemistry,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,China [4]Department of Chemistry,Johns Hopkins University,Baltimore MD,USA

出　　处：《Natural Products and Bioprospecting》2012年第2期59-64,共6页应用天然产物（英文）

摘　　要：P-Glycoprotein/MDR1 represents an important component of the blood brain barrier and contributes to multidrug resistance.We investigated two derivatives of the anti-malarial artemisinin,SM616 and GHP-AJM-3/23,concerning their ability to interact with P-glycoprotein.The ability of the two compounds to inhibit P-glycoprotein(P-gp)activity was examined in sensitive CCRF-CEM and P-gp over-expressing and multidrug-resistant CEM/ADR5000 cells as well as in porcine brain capillary endothelial cells(PBCEC)by means of calcein-AM assays.Verapamil as well-known P-gp inhibitor was used as control drug.CEM/ADR5000 cells exhibited cross-resistance to GHP-AJM-3/23,but slight collateral sensitivity to SM616.Furthermore,SM616 inhibited calcein efflux both in CEM/ADR5000 and PBCEC,whereas GHP-AJM-3/23 did only increase calcein fluorescence in PBCEC,but not CEM/ADR5000.This may be explained by the fact that CEM/ADR5000 only express P-gp but not other ATP-binding cassette transporters,whereas PBCEC are known to express several ABC transporters and calcein is transported by more than one ABC transporter.Hence,SM616 may be the more specific P-gp inhibitor.In conclusion,the collateral sensitivity of SM616 as well as the inhibition of calcein efflux in both CEM/ADR5000 cells and PBCEC indicate that this compound may be a promising P-gp inhibitor to treat cancer therapy and to overcome the blood brain barrier.

关 键 词：blood brain barrier CALCEIN multidrug resistance P-GLYCOPROTEIN 

分 类 号：R73[医药卫生—肿瘤]