Quercetin potentiates the effect of adriamycin in a multidrug-resistant MCF-7 human breast-cancer cell line: P-glycoprotein as a possible target

Abstract

This study demonstrates that the flavonoid quercetin (Q), a plant-derived compound with low toxicity in vivo, greatly potentiates the growth-inhibitory activity of Adriamycin (ADR) on MCF-7 ADR-resistant human breast cancer cells. The effect of Q was dose-dependent at concentrations ranging between 1 and 10 microM. Since ADR resistance in these cells is associated with the expression of high levels of P-glycoprotein (Pgp), we evaluated the effect of Q and related flavonoids of Pgp activity in cytofluorographic efflux experiments with the fluorescent dye rhodamine 123 (Rh 123). Our results indicate that Q and 3-OMe Q (3',4',7-trimethoxyquercetin) but not the 3-rhamnosylglucoside of Q (rutin) inhibit the Pgp pump-efflux activity in a dose-related manner. Moreover, 10 microM Q reduces the expression of the immunoreactive Pgp in MCF-7 ADR-resistant cells as evaluated by cytofluorimetric assay. In conclusion, these findings provide a further biological basis for the potential therapeutic application of Q as an anti-cancer drug either alone or in combination with ADR in multidrug-resistant breast tumor cells.

Flavonoids: A class of modulators with bifunctional interactions at vicinal ATP- and steroid-binding sites on mouse P-glycoprotein

“…All flavonoids reported to modulate drug efflux in MDR cancer cells, such as kaempferol, galangin, quercetin and hydrophobic derivatives, and genistein (11,12,28) are shown here to bind, with similar affinities and relative efficiencies, to purified cytosolic H 6 -NBD2. In addition, rutin, a glycosylated flavonoid that did not behave as a modulator of cellular MDR phenotype (12), exhibits a very low-affinity binding for H 6 -NBD2.…”

“…In addition, rutin, a glycosylated flavonoid that did not behave as a modulator of cellular MDR phenotype (12), exhibits a very low-affinity binding for H 6 -NBD2. Flavones, which are known as the best modulators, especially methoxylated derivatives, indeed display higher affinity for quenching H 6 -NBD2 fluorescence as compared with isoflavones and flavanones.…”

“…The modulatory efficiency of hydrophobic steroids could be recently correlated to their high-affinity binding to N-terminal cytosolic domain, close to the ATP-binding site (10). Flavonoids have also been described as modulators, but contradictory effects were reported with different multidrugresistant cell lines: quercetin, kaempferol, and galangin were found to increase adriamycin efflux from HCT-15 colon cells (11), whereas quercetin and a methoxylated derivative inhibited rhodamine 123 efflux and reverted MDR in MCF-7 breast cells (12). Quercetin was indeed shown to bind to purified P-glycoprotein and to efficiently inhibit its activity (13).…”

Bioavailability enhancers of herbal origin: An overview

“…The absorption of diltiazem in the intestinal mucosa was inhibited by P-glycoprotein efflux pump [42,43] . The increased AUCs and C(max) of diltiazem by pretreatment of quercetin might have been resulted from the inhibition of the P-glycoprotein efflux pump and the metabolizing enzyme, CYP3A4 in the intestinal mucosa [44,45] and restraint of the metabolizing enzyme, CYP3A4 [46] .…”

Quercitrin suppresses hepatocellular carcinoma metastasis and angiogenesis by targeting the Nrf2 signaling pathway

“…Although previous researches demonstrate that few fl avonoids exhibit anti-cancer in HCC, the anticancer roles of quercetin in HCC remain not well be elucidated [20]. Therefore, this present study aimed to determine whether quercetin could inhibit the growth and metastasis of HCC [21]. Additionally, we attempted to uncover the underlying cellular and molecular anticancer mechanisms of quercetin.…”