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Flavonoid structure-activity studies identify 6-prenylchrysin and tectochrysin as potent and specific inhibitors of breast cancer resistance protein ABCG2.

Abstract
Overexpression of breast cancer resistance protein ABCG2 confers multidrug resistance in cancer cells. The GF120918-sensitive drug efflux activity of human wild-type (R482) ABCG2-transfected cells was used for rational screening of inhibitory flavonoids and establishment of structure-activity relationships. Flavones were found more efficient than flavonols, isoflavones, and flavanones. Differentially substituted flavone derivatives indicated positive OH effects at position 5, in contrast to positions 3 and 7. A methoxy at position 7 was slightly positive in tectochrysin, whereas a strong positive effect was produced by prenylation at position 6. The potency of 6-prenylchrysin was comparable with that of GF120918 (IC50 = 0.3 micromol/L). Both 6-prenylchrysin and tectochrysin seemed specific for ABCG2 because no interaction was detected with either P-glycoprotein or MRP1. The ABCG2 resistance profile in vitro is altered by mutation at amino acid 482. The R482T mutation limited the effect of prenylation on ABCG2 inhibition. Whereas GF120918 strongly inhibited the ATPase activity of wild-type ABCG2, neither 6-prenylchrysin nor tectochrysin altered the activity. In contrast, all three inhibitors stimulated the ATPase activity of mutant ABCG2. 6-Prenylchrysin at 0.5 micromol/L efficiently sensitized the growth of wild-type ABCG2-transfected cells to mitoxantrone, whereas higher concentrations were required for the mutant ones. In contrast, 1 micromol/L tectochrysin was sufficient to fully sensitize mutant ABCG2-transfected cells, whereas higher concentrations were required for the wild-type ones. Both flavones exhibited a lower intrinsic cytotoxicity than GF120918 and were apparently not transported by ABCG2. 6-Prenylchrysin and tectochrysin therefore constitute new and promising inhibitors for the reversal of ABCG2-mediated drug transport.
AuthorsAbdelhakim Ahmed-Belkacem, Alexandre Pozza, Francisco Muñoz-Martínez, Susan E Bates, Santiago Castanys, Francisco Gamarro, Attilio Di Pietro, José M Pérez-Victoria
JournalCancer research (Cancer Res) Vol. 65 Issue 11 Pg. 4852-60 (Jun 01 2005) ISSN: 0008-5472 [Print] United States
PMID15930306 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • 6-prenylchrysin
  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Acridines
  • Benzimidazoles
  • Flavonoids
  • Multidrug Resistance-Associated Proteins
  • Neoplasm Proteins
  • Rhodamines
  • Tetrahydroisoquinolines
  • rhodamine 6G
  • tectochrysin
  • Mitoxantrone
  • Adenosine Triphosphatases
  • Elacridar
  • bisbenzimide ethoxide trihydrochloride
  • multidrug resistance-associated protein 1
Topics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters (antagonists & inhibitors, genetics)
  • Acridines (pharmacology)
  • Adenosine Triphosphatases (metabolism)
  • Benzimidazoles (pharmacokinetics)
  • Cell Line
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Flavonoids (chemistry, pharmacology)
  • Humans
  • Mitoxantrone (pharmacokinetics, pharmacology)
  • Multidrug Resistance-Associated Proteins (metabolism)
  • Neoplasm Proteins (antagonists & inhibitors, genetics)
  • Rhodamines (pharmacokinetics)
  • Structure-Activity Relationship
  • Tetrahydroisoquinolines (pharmacology)
  • Transfection

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