Inhibition of P-glycoprotein by two artemisinin derivatives

doi:10.1007/s13659-012-0006-3

Natural Products and Bioprospecting ›› 2012, Vol. 2 ›› Issue (2): 59-64.DOI: 10.1007/s13659-012-0006-3

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Inhibition of P-glycoprotein by two artemisinin derivatives

Babette STEGLICH^a,b, Anne MAHRINGER^b, Ying LI^c, Gary H. POSNER^d, Gert FRICKER^b, Thomas EFFERTH^a

a Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 551 Mainz, Germany;
b Institute of Pharmacy and Molecular Biotechnology, Karl Ruprecht University, Heidelberg, Germany;
c Department of Synthetic Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China;
d Department of Chemistry, Johns Hopkins University, Baltimore MD, USA

Received:2012-01-23 Revised:2012-02-29 Online:2018-02-11 Published:2012-04-24

Inhibition of P-glycoprotein by two artemisinin derivatives

Babette STEGLICH^a,b, Anne MAHRINGER^b, Ying LI^c, Gary H. POSNER^d, Gert FRICKER^b, Thomas EFFERTH^a

a Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 551 Mainz, Germany;
b Institute of Pharmacy and Molecular Biotechnology, Karl Ruprecht University, Heidelberg, Germany;
c Department of Synthetic Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China;
d Department of Chemistry, Johns Hopkins University, Baltimore MD, USA

通讯作者: Thomas EFFERTH,E-mail:efferth@uni-mainz.de

Abstract

Abstract: 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.

Key words: blood brain barrier, calcein, multidrug resistance, P-glycoprotein

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

Babette STEGLICH, Anne MAHRINGER, Ying LI, Gary H. POSNER, Gert FRICKER, Thomas EFFERTH. Inhibition of P-glycoprotein by two artemisinin derivatives[J]. Natural Products and Bioprospecting, 2012, 2(2): 59-64.

Babette STEGLICH, Anne MAHRINGER, Ying LI, Gary H. POSNER, Gert FRICKER, Thomas EFFERTH. Inhibition of P-glycoprotein by two artemisinin derivatives[J]. 应用天然产物, 2012, 2(2): 59-64.

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Inhibition of P-glycoprotein by two artemisinin derivatives

Inhibition of P-glycoprotein by two artemisinin derivatives

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