Modulation of multidrug resistance protein 1 (MRP1/ABCC1)-mediated multidrug resistance by bivalent apigenin homodimers and their derivatives

Iris L K Wong, Kin Fai Chan, Hing Tsang Ka, Yin Lam Chi, Yunzhe Zhao, Hang Chan Tak, Ming Cheung Chow

Research output: Journal article publicationJournal articleAcademic researchpeer-review

74 Citations (Scopus)


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 Ki = 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.
Original languageEnglish
Pages (from-to)5311-5322
Number of pages12
JournalJournal of Medicinal Chemistry
Issue number17
Publication statusPublished - 10 Sep 2009

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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