Phytochemistry Reviews

, Volume 1, Issue 3, pp 325–332 | Cite as

Isoprenoid flavonoids are new leads in the modulation of chemoresistance

  • Denis Barron
  • Attilio Di Pietro
  • Charles Dumontet
  • David B. McIntosh


Flavonoid compounds are able to bind to P-glycoprotein (P-gp), a transporter involved in chemoresistance of cancer cells. This interaction involves, at least in part, two overlapping sites in the cytosolic domains of P-gp, the ATP site and a hydrophobic steroid-binding site. We have studied the structure-activity relationships toward binding to P-gp. Modification of the substitution pattern of the flavonoid ring by hydroxylation, methoxylation or introduction of nitrogen-containing substituents had little effect. On the contrary, the presence of a 3-hydroxyl (flavonols), and especially of a C-isoprenoid chain increased the affinity of flavonoids towards P-gp. More detailed examination of the interaction with the ATP site was conducted through inhibition by flavonoids of the photolabeling by radioactive 8-azido-TNP-ATP. Only simple flavonols were demonstrated to bind to the ATP site. When position 3 was free (flavones) or when a hydrophobic C-prenyl substituent was present, interaction was rather directed to the hydrophobic site. A number of flavonoid compounds were tested for their ability to modulate multidrug resistance in resistant leukemic K562/R7 cells. Again, prenyl flavonoids were potent modulators. Simple flavonoids were ineffective in this model. The beneficial effect of prenylation was lower in polyhydroxylated compounds, suggesting a crucial role of hydrophobicity in P-gp modulation.

chemoresistance isoprenoid flavonoids P-glycoprotein prenyl flavones 


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Copyright information

© Kluwer Academic Publishers 2002

Authors and Affiliations

  • Denis Barron
    • 1
  • Attilio Di Pietro
    • 2
  • Charles Dumontet
    • 3
  • David B. McIntosh
    • 4
  1. 1.Laboratoire des Produits Naturels, B^atiment ChevreulUniversitéVilleurbanneFrance
  2. 2.Laboratoire des Protéines de Résistance aux Agents Chimiothérapeutiques, IBCPLyonFrance
  3. 3.Laboratoire de Cytologie Analytique, Faculté de MédecineLyonFrance
  4. 4.Department of Chemical PathologyUniversity of Cape Town Medical School, ObservatorySouth Africa

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