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-resista nt (MDR) cells, developed from human breast cancer MCF-7 cells by expo sure to Adriamycin, to investigate the effects of flavonoids on P-gp-m ediated efflux mechanisms for chemical carcinogens. We previously show ed that MDR cells derived from exposure to Adriamycin are cross-resist ant to a chemical carcinogen, benzo(a)pyrene, due to its cellular effl ux 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 ani mals. In our attempt to find naturally occurring dietary compounds whi ch may stimulate the P-gp-mediated efflux of carcinogens, we found tha t certain flavonols, kaempferol, quercetin, and galangin, are potent s timulators of the P-gp-mediated efflux of 7,12-dimethylbenz(a)-anthrac ene. The increased efflux decreased the cellular burden of 7,12-dimeth ylbenz(a)anthracene. Since these flavonol compounds are widely distrib uted in fruits and vegetables, their stimulatory effect on P-gp may be a mechanism relevant to carcinogenesis and the observed lowered cance r risk in humans with higher dietary intake of fruits and vegetables.