ALL-TRANS-RETINOIC ACID METABOLITES SIGNIFICANTLY INHIBIT THE PROLIFERATION OF MCF-7 HUMAN BREAST-CANCER CELLS IN-VITRO

All-irans-retinoic acid (ATRA) is well known to inhibit the proliferat ion of human breast cancer cells. Much less is known about the antipro liferative activity of the naturally occurring metabolites and isomers of ATRA. In the present study, we investigated the antiproliferative activity of ATRA, its physiological catabolites 4-oxo-ATRA and 5,6-epo xy-ATRA and isomers 9-cis-RA and 13-cis-RA in MCF-7 human breast cance r cells by bromodeoxyuridine incorporation. MCF-7 cells were grown in steroid-and retinoid-free medium supplemented with growth factors. Und er these culture conditions, ATRA and its naturally occurring cataboli tes and isomers showed significant antiproliferative activity in MCF-7 cells in a concentration-dependent manner (10(-11) M to 10(-6) M). Th e antiproliferative activity of ATRA catabolites and isomers was equal to that of the parent compound ATRA at concentrations of 10(-8) M and 10(-7) M. Only at 10(-6) M were the catabolites and the stereoisomer 13-cis-RA less potent. The stereoisomer 9-cis-RA was as potent as ATRA at all concentrations tested (10(-11) M to 10(-6) M). In addition, we show that the catabolites and isomers were formed from ATRA to only a limited extent. Together, our findings suggest that in spite of their high antiproliferative activity the catabolites and isomers of ATRA c annot be responsible for the observed growth inhibition induced by ATR A.