Isoprenoid flavonoids are new leads in the modulation of chemoresistance
- 105 Downloads
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.
Unable to display preview. Download preview PDF.
- Di Pietro A, Conseil G, Perez-Victoria JM, Dayan G, Baubichon-Cortay H, Trompier D, Steinfels E, Jault JM, de Wet H, Maitrejean M, Comte G, Boumendjel A, Mariotte AM, Dumontet C, McIntosh D, Goffeau A, Castanys S, Gamarro F & Barron D (2002) Modulation by flavonoids of cell multidrug resistance mediated by P-glycoprotein and related ABC transporters. Cell Mol. Life Sci. 59: 307–322.PubMedCrossRefGoogle Scholar
- Middledon Jr E, Kandaswami C & Theoharides TC (2000) The effects of plant flavonoids on mammalian cells: Implications for inflammation, heart disease, and cancer. Pharmacol. Rev. 52: 673–751.Google Scholar