Flavonol-stimulated efflux of 7,12-dimethylbenz(a)anthracene in multidrug-resistant breast cancer cells.
We used a series of P-glycoprotein (P-gp) expressing multidrug-resistant (MDR) cells, developed from human breast cancer MCF-7 cells by exposure to Adriamycin, to investigate the effects of flavonoids on P-gp-mediated efflux mechanisms for chemical carcinogens. We previously showed that MDR cells derived from exposure to Adriamycin are cross-resistant to a chemical carcinogen, benzo(a)pyrene, due to its cellular efflux by the P-gp-mediated putative drug efflux pump. Our current studies extended this observation to another polycyclic aromatic hydrocarbon, 7,12-dimethylbenz(a)anthracene, known to induce mammary tumors in animals. In our attempt to find naturally occurring dietary compounds which may stimulate the P-gp-mediated efflux of carcinogens, we found that certain flavonols, kaempferol, quercetin, and galangin, are potent stimulators of the P-gp-mediated efflux of 7,12-dimethylbenz(a)-anthracene. The increased efflux decreased the cellular burden of 7,12-dimethylbenz(a)anthracene. Since these flavonol compounds are widely distributed in fruits and vegetables, their stimulatory effect on P-gp may be a mechanism relevant to carcinogenesis and the observed lowered cancer risk in humans with higher dietary intake of fruits and vegetables.
Phang
J M
JM
Laboratory of Nutritional and Molecular Regulation, National Cancer Institute, NIH, Frederick, Maryland 21702.
Poore
C M
CM
Lopaczynska
J
J
Yeh
G C
GC
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000378:metabolism*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001943:Breast Neoplasms / Q000378:metabolism*; D002352:Carrier Proteins / Q000502:physiology; D004032:Diet; D004351:Drug Resistance; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D044948:Flavonols; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D005419:Flavonoids; D044948:Flavonols; D008562:Membrane Glycoproteins; D015127:9,10-Dimethyl-1,2-benzanthracene