Inhibition of P-glycoprotein by natural products in human breast cancer cells.
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.
Chung
Soo Yeon
SY
College of Pharmacy, Ewha Womans University, Seoul 120-750, Korea.
Sung
Min Kyung
MK
Kim
Na Hyung
NH
Jang
Jung Ok
JO
Go
Eun Jung
EJ
Lee
Hwa Jeong
HJ
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*
D018435:ATP Binding Cassette Transporter, Subfamily B; D000903:Antibiotics, Antineoplastic; D005419:Flavonoids; D012838:Silymarin; D011794:Quercetin; D019833:Genistein; C004541:biochanin A; D003630:Daunorubicin