<i>C</i>-Isoprenylation of Flavonoids Enhances Binding Affinity toward P-Glycoprotein and Modulation of Cancer Cell Chemoresistance

Comte, Gilles; Daskiewicz, Jean-Baptiste; Bayet, Christine; Conseil, Gwenaëlle; Viornery-Vanier, § Armelle; Dumontet, Charles; Pietro, and Attilio Di; Barron, Denís

doi:10.1021/jm991128y

Cited by 108 publications

(97 citation statements)

References 19 publications

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“…Mitoxantrone and rhodamine 6G were purchased from Sigma (L'isle d'Abeau, Chesnes, France), and nonprenylated flavonoids from Extrasynthèse (Genay, France). Prenylated derivatives of chrysin were obtained as previously described (15,28). GF120918 was provided by GlaxoSmithKline (Madrid, Spain).…”

Section: Methodsmentioning

confidence: 99%

Flavonoid Structure-Activity Studies Identify 6-Prenylchrysin and Tectochrysin as Potent and Specific Inhibitors of Breast Cancer Resistance Protein ABCG2

et al. 2005

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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 (IC 50 = 0.3 Mmol/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 Mmol/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 Mmol/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. (Cancer Res 2005; 65(11): 4852-60)

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Section: Methodsmentioning

confidence: 99%

Flavonoid Structure-Activity Studies Identify 6-Prenylchrysin and Tectochrysin as Potent and Specific Inhibitors of Breast Cancer Resistance Protein ABCG2

et al. 2005

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“…We have studied flavones, flavonols, chalcones and other phenolic compounds, and have identified the structural criteria required for a high binding-affinity. [9][10][11][12][13] Continuing our efforts in identifying Pgp-mediated MDR modulators, we wish to report here for the first time the binding of aurones, which constitute a naturally-occurring subclass of flavonoids frequently found in plants, where they contribute to the coloration of fruits and flowers (Fig. 1).…”

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confidence: 99%

4-Hydroxy-6-methoxyaurones with High-Affinity Binding to Cytosolic Domain of P-Glycoprotein.

Boumendjel

Beney

Deka

et al. 2002

CHEMICAL & PHARMACEUTICAL BULLETIN

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A series of 4-hydroxy-6-methoxyaurones and 4,6-dimethoxyaurones has been synthesised and tested for their binding affinity toward the nucleotide-binding domain of P-glycoprotein, an ABC (ATP-Binding Cassette) transporter which mediates the resistance of cancer cells to chemotherapy. These compounds differ from each other by the nature of the substituent on the aurone B-ring. The binding affinity seems to be linked to the nature of the substituent, as well as to the presence or the absence of a hydroxy group at position 4. The most active compounds were 4-bromo-4-hydroxy-6-methoxyaurone and 4-hydroxy-4-iodo-6-methoxyaurone.

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“…Park et al (14) indicated that 6,8-disubstituted chrysin derivatives, which were obtained from naturally occurring ChR by halogenation, showed as strong an inhibitory activation of PGE2 production from LPS-induced RAW 264.7 cells as wogonin, a well-known natural flavone that has strong and selective COX-2 inhibitory activity. Comte et al (15) reported that through alkylation, the hydrophobic degree of ChR is increased, the KD value is decreased and the binding affinity toward P-glycoprotein (P-gp) in the cell is enhanced. We previously showed that 5,7-dihydroxy-8-nitrochrysin (NOC) was obtained through synthesization (16).…”

Section: Introductionmentioning

confidence: 99%

Induction of apoptosis by 5,7-dihydroxy-8-nitrochrysin in breast cancer cells: The role of reactive oxygen species and Akt

Zhao

Tian²,

Cao³

et al. 2010

Int J Oncol

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Abstract. 5,7-dihydroxy-8-nitrochrysin (NOC), a novel synthetic chrysin analogue, induces apoptosis in human cancer cells. We previously demonstrated that NOC possesses stronger cytotoxicity towards human colon carcinoma and human gastric carcinoma cells than chrysin. Herein, we demonstrate the mechanism by which NOC preferentially suppresses the viability of the MDA-MB-453 human breast cancer cell line (ER negative, Her2 overexpressing) and moderately suppresses the viability of the MCF-7 cell line (ER positive, Her2 low), but has little effect on the immortalized non-cancerous HBL-100 breast cell line (ER positive, Her2 low). Moreover, the results of our studies, for the first time, provide mechanistic evidence that NOC induces apoptosis by the generation of reactive oxygen species and Akt dephosphorylation. Our findings highlight a new mechanism responsible for NOC-induced apoptosis, and raise the possibility that NOC might be promising as a candidate for human breast cancer therapy.

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C-Isoprenylation of Flavonoids Enhances Binding Affinity toward P-Glycoprotein and Modulation of Cancer Cell Chemoresistance

Cited by 108 publications

References 19 publications

Flavonoid Structure-Activity Studies Identify 6-Prenylchrysin and Tectochrysin as Potent and Specific Inhibitors of Breast Cancer Resistance Protein ABCG2

Flavonoid Structure-Activity Studies Identify 6-Prenylchrysin and Tectochrysin as Potent and Specific Inhibitors of Breast Cancer Resistance Protein ABCG2

4-Hydroxy-6-methoxyaurones with High-Affinity Binding to Cytosolic Domain of P-Glycoprotein.

Induction of apoptosis by 5,7-dihydroxy-8-nitrochrysin in breast cancer cells: The role of reactive oxygen species and Akt

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