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

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• 作者：Iris L. K. Wong ; Kin-Fai Chan ; Ka Hing Tsang ; Chi Yin Lam ; Yunzhe Zhao ; Tak Hang Chan ; Larry Ming Cheung Chow
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：September 10, 2009
• 年：2009
• 卷：52
• 期：17
• 页码：5311-5322
• 全文大小：973K
• 年卷期：v.52,no.17(September 10, 2009)
• ISSN：1520-4804

文摘

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.