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) or 7-methyl (5e, 5f) substitution on the ring A of flavonoid dimers have the highest modulating activity for DOX against MRP1 with an EC(50) ranging from 73 to 133 nM. At 0.5 microM, 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 microM. 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.
Wong
Iris L K
IL
Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hum, Hong Kong, SAR.
Chan
Kin-Fai
KF
Tsang
Ka Hing
KH
Lam
Chi Yin
CY
Zhao
Yunzhe
Y
Chan
Tak Hang
TH
Chow
Larry Ming Cheung
LM
D047310:Apigenin / Q000737:chemistry* / Q000494:pharmacology*; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D006878:Hydroxides / Q000737:chemistry; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013329:Structure-Activity Relationship
D047310:Apigenin; D004317:Doxorubicin; D005047:Etoposide; D006878:Hydroxides; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C031356:hydroxide ion; C421109:multidrug resistance-associated protein 1