THE ANTIPROLIFERATIVE ACTIVITY OF ALL-TRANS-RETINOIC ACID CATABOLITESAND ISOMERS IS DIFFERENTIALLY MODULATED BY LIAROZOLE-FUMARATE IN MCF-7 HUMAN BREAST-CANCER CELLS

The clinical use of all-trans-retinoic acid (ATRA) in the treatment of cancer is significantly hampered by the prompt emergence of resistanc e, believed to be caused by increased ATRA catabolism. Inhibitors of A TRA catabolism may therefore prove valuable for cancer therapy. Liaroz ole-fumarate is an anti-tumour drug that inhibits the cytochrome P450- dependent catabolism of ATRA. ATRA, but also its naturally occurring c atabolites, 4-oxo-ATRA and 5,6-epoxy-ATRA, as well as its stereoisomer s, 9-cis-RA and 13-cis-RA, show significant antiproliferative activity in MCF-7 human breast cancer cells. To further elucidate its mechanis m of action, we investigated whether liarozole-fumarate was able to en hance the antiproliferative activity of ATRA catabolites and isomers. Liarozole-fumarate alone up to a concentration of 10(-6) M had no effe ct on MCF-7 cell proliferation. However, in combination with ATRA or t he ATRA catabolites, liarozole-fumarate (10(-6) M) significantly enhan ced their antiproliferative activity. On the contrary, liarozole-fumar ate (10(-6) M) was not able to potentiate the antiproliferative activi ty of the ATRA stereoisomers, most probably because of the absence of cytochrome P450-dependent catabolism. Together, these findings show th at liarozole-fumarate acts as a versatile inhibitor of retinoid catabo lism in that it not only blocks the breakdown of ATRA, but also inhibi ts the catabolic pathway of 4-oxo-ATRA and 5,6-epoxy-ATRA, thereby enh ancing their antiproliferative activity.