title: Inhibition of P-glycoprotein by natural products in human breast cancer cells.
abstract: Multidrug resistance (MDR) is one of the most significant obstacles in cancer chemotherapy. One of the mechanisms involved in the development of MDR is the over-expression of P-glycoprotein (P-gp). It is widely known that natural compounds found in vegetables, fruits, plant-derived beverages and herbal dietary supplements not only have anticancer properties, but may also modulate P-gp activity. Therefore, the purpose of this investigation was to examine the effects of naturally occurring products on P-gp function in human breast cancer cell lines, MCF-7 (sensitive) and MCF-7/ADR (resistant). The accumulation of daunomycin (DNM), a P-gp substrate, was greater in the sensitive cells compared to the resistant cells, while the efflux of DNM was higher in the resistant cells compared to the sensitive cells over a period of 2 h. The IC50 value of DNM in the resistant cells was about 22 times higher than that in the sensitive cells, indicating an over-expression of P-gp in the resistant cells, MCF-7/ADR. All of the compounds tested, with the exception of fisetin, significantly decreased the IC50 value of DNM. Biochanin A showed the greatest increase in [3H]-DNM accumulation, increasing by 454.3 +/- 19.5% in the resistant cells, whereas verapamil, the positive control, increased the accumulation by 229.4 +/- 17.6%. Also, the accumulation of [3H]-DNM was increased substantially by quercetin and silymarin while it was reduced by fisetin. Moreover, biochanin A, silymarin, and naringenin significantly decreased DNM efflux from MCF-7/ADR cells compared with the control. These results suggest that some flavonoids such as biochanin A and silymarin may reverse MDR by inhibiting the P-gp function.
authors.affiliation: College of Pharmacy, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Soo Yeon
authors.initials: SY
authors.lastname: Chung
authors.forename: Min Kyung
authors.initials: MK
authors.lastname: Sung
authors.forename: Na Hyung
authors.initials: NH
authors.lastname: Kim
authors.forename: Jung Ok
authors.initials: JO
authors.lastname: Jang
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Go
authors.forename: Hwa Jeong
authors.initials: HJ
authors.lastname: Lee
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000378:metabolism* / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003630:Daunorubicin / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005419:Flavonoids / Q000494:pharmacology*; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D011794:Quercetin / Q000494:pharmacology*; D012838:Silymarin / Q000494:pharmacology*
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000903:Antibiotics, Antineoplastic; D005419:Flavonoids; D012838:Silymarin; D011794:Quercetin; D019833:Genistein; C004541:biochanin A; D003630:Daunorubicin