Flavonoid dimers are highly potent killers of multidrug resistant cancer cells overexpressing MRP1

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• 作者：Lauriane Dury^a ; ¹ ; ^{lauriane.dury@gmail.com} ; Rachad Nasr^a ; ¹ ; ^{rachad.nasr@ibcp.fr} ; Doriane Lorendeau^a ; ^{doriane.lorendeau@gmail.com} ; Elisabeta Comsa^a ; ^{elisabetacomsa@yahoo.com} ; Iris Wong^b ; ^{iris.l.k.wong@polyu.edu.hk} ; Xuezhen Zhu^b ; ^{duomiantixiaozhen@gmail.com} ; Kin-Fai Chan^b ; ^{kfchan@polyu.edu.hk} ; Tak-Hang Chan^b ; ^{tak-hang.chan@polyul.edu.hk} ; Larry Chow^b ; ^{bclchow@polyu.edu.hk} ; Pierre Falson^a ; ^{pierre.falson@ibcp.fr} ; Attilio Di Pietro^a ; ^{ac.dipietro2@gmail.com} ; Hé ; lè ; ne Baubichon-Cortay^a ; ^{helene.cortay@ibcp.fr}
• 关键词：ABC ; ATP binding cassette ; MDR ; Multidrug Resistance ; MRP1 and MRP2 ; Multidrug Resistance Protein 1 and 2 ; BHK-21 ; Baby Hamster Kidney 21 ; MTT ; 3-[4 ; 5-dimé ; thylthiazol-2yl]-2 ; 5-diphenyltetrazolium bromide ; GSH ; reduced glutathione ; SR ; selective ratio ; PBS ; phosphate buffer salt ; SD ; standard deviation
• 刊名：Biochemical Pharmacology
• 出版年：2017
• 出版时间：15 January 2017
• 年：2017
• 卷：124
• 期：Complete
• 页码：10-18
• 全文大小：759 K
• 卷排序：124

文摘

MRP1 overexpression in multidrug-resistant cancer cells has been shown to be responsible for collateral sensitivity to some flavonoids that stimulate a huge MRP1-mediated GSH efflux. This massive GSH depletion triggers the death of these cancer cells. We describe here that bivalent flavonoid dimers strikingly stimulate such MRP1-mediated GSH efflux and trigger a 50–100 fold more potent cell death than their corresponding monomers. This selective and massive cell death of MRP1-overexpressing cells (both transfected and drug-selected cell lines) is no longer observed either upon catalytic inactivation of MRP1 or its knockdown by siRNA. The best flavonoid dimer, 4e, kills MRP1-overexpressing cells with a selective ratio higher than 1000 compared to control cells and an EC50 value of 0.1 μM, so far unequaled as a collateral sensitivity agent targeting ABC transporters. This result portends the flavonoid dimer 4e as a very promising compound to appraise in vivo the therapeutic potential of collateral sensitivity for eradication of MRP1-overexpressing chemoresistant cancer cells in tumors.