Modulation of Multidrug Resistance Protein 1 (MRP1/ABCC1)-Mediated Multidrug Resistance by Bivalent Apigenin Homodimers and Their Derivatives

Here we showed that bivalency approach is effective in modulating multidrug resistance protein 1 (MRP1/ABCC1)-mediated doxorubicin (DOX) and etoposide (VP16) resistance in human 2008/MRP1 ovarian carcinoma cells. Flavonoid dimers bearing five or six ethylene glycol (EG) units with 6-methyl (4e, 4f)...

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Published in:	Journal of medicinal chemistry Vol. 52; no. 17; pp. 5311 - 5322
Main Authors:	Wong, Iris L. K, Chan, Kin-Fai, Tsang, Ka Hing, Lam, Chi Yin, Zhao, Yunzhe, Chan, Tak Hang, Chow, Larry Ming Cheung
Format:	Journal Article
Language:	English
Published:	Columbus, OH American Chemical Society 10-09-2009
Subjects:	Antineoplastic agents Apigenin - chemistry Apigenin - pharmacology Binding, Competitive Biological and medical sciences Cell Line, Tumor Dimerization Dose-Response Relationship, Drug Doxorubicin - metabolism Doxorubicin - pharmacology Drug Resistance, Multiple - drug effects Etoposide - pharmacology General aspects Humans Hydroxides - chemistry Intracellular Space - drug effects Intracellular Space - metabolism Medical sciences Multidrug Resistance-Associated Proteins - antagonists & inhibitors Multidrug Resistance-Associated Proteins - metabolism Pharmacology. Drug treatments Structure-Activity Relationship Antineoplastic agent Podophyllotoxin derivatives Cytotoxicity Oligomer Flavonoid Doxorubicin Ethylene oxide polymer Ovary Polyphenol Isomerases Structure activity relation Multiple resistance Inhibition Chemical synthesis Antimitotic Tumor cell Carrier protein Human Transmembrane protein DNA topoisomerase (ATP-hydrolysing) Drug combination Enzyme Enzyme inhibitor Etoposide In vitro Cell line Flavone derivatives Reversibility Anthracyclins Dimer Multidrug resistance protein 1 ABC transporter Chemosensitizing agent
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Summary:	Here we showed that bivalency approach is effective in modulating multidrug resistance protein 1 (MRP1/ABCC1)-mediated doxorubicin (DOX) and etoposide (VP16) resistance in human 2008/MRP1 ovarian carcinoma cells. Flavonoid dimers bearing five or six ethylene glycol (EG) units with 6-methyl (4e, 4f) or 7-methyl (5e, 5f) substitution on the ring A of flavonoid dimers have the highest modulating activity for DOX against MRP1 with an EC50 ranging from 73 to 133 nM. At 0.5 μM, the flavonoid dimer 4e was sufficient to restore DOX accumulation in 2008/MRP1 to parental 2008/P level. Lineweaver−Burk and Dixon plot suggested that it is likely a competitive inhibitor of DOX transport with a K i = 0.2 μM. Our data suggest that flavonoid dimers have a high affinity toward binding to DOX recognition site of MRP1. This results in inhibiting DOX transport, increasing intracellular DOX retention, and finally resensitizing 2008/MRP1 to DOX. The present study demonstrates that flavonoid dimers can be employed as an effective modulator of MRP1-mediated drug resistance in cancer cells.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm900194w