7-O-geranylquercetin contributes to reverse P-gp-mediated adriamycin resistance in breast cancer.

AIMS:To investigate the effect of 7-O-geranylquercetin (GQ), a derivative of quercetin (Q), on reversing drug resistance in breast cancer MCF-7/ADR cells and reveal the mechanisms related to P-glycoprotein (P-gp). MAIN METHODS:Cell viability was determined by MTT assay. Accumulation of adriamycin (ADR) in cells was determined by confocal fluorescence microscope and microplate reader while that of rhodamine (Rh) was measured by flow cytometry. Expression levels of P-gp and MDR1 gene in cells were detected by western blot and Real-Time PCR, respectively. Molecular docking of GQ and Q with P-gp was conducted using AutoDock program. Xenograft model was established by inoculating MCF-7/ADR cells in BALB/c-nude mice. Tumor bearing mice were administered with ADR via tail vein injection and/or GQ (Q) by gavage. Expression levels of P-gp in tissues were detected by western blot and immunohistochemistry. KEY FINDINGS:GQ could reverse drug resistance of MCF-7/ADR cells to ADR. GQ inhibited the efflux of ADR by down-regulating the expression of P-gp protein and its encoding gene MDR1 in MCF-7/ADR cells. Molecular modeling showed that GQ matched with P-gp better than Q. GQ enhanced the antitumor effects of ADR and decreased the expression of P-gp in mice and its activities were higher than that of Q. GQ could reverse drug resistance of MCF-7/ADR cells by down-regulating the expression of P-gp in vitro and in vivo. SIGNIFICANCES:The reversal effect of GQ on P-gp-mediated drug resistance indicates its potential as a reversal agent for drug resistance in cancer chemotherapy.