LIAROZOLE POTENTIATES THE ALL-TRANS-RETINOIC ACID-INDUCED STRUCTURAL REMODELING IN HUMAN BREAST-CARCINOMA MCF-7 CELLS IN-VITRO

Liarozole inhibits cytochrome P-450-dependent enzymes that play a key role in all-trans-retinoic acid (ATRA) catabolism, In MCF-7 cells, lia rozole potentiates the antiproliferative effects of ATRA. The present study demonstrates this synergistic effect on cell differentiation of MCF-7 cell cultures as measured by immunocytochemistry for cytokeratin s 8, 18, and 19, actin, E-cadherin, desmoglein and desmoplakins I & II , ATRA concentration-dependentlg (10(-8)m -10(-6)m) induced changes in actin stress fibers and cytokeratin intermediate filaments, These cha nges were accompanied by a more obvious interaction of these filaments ,vith junctional complexes, Surface area and volume of the MCF-7 cells increased markedly after ATRA exposure, with extensive, filopodia for mation, Iiarozole (10(-6)m) alone had no effect on cell morphology: cy tokeratin or actin organization, or on cellular junctions, In combinat ion with ATRA (10(-9)m and 10(-8)m), liarozole potentiated the ATRA-in duced effects, The MCF-7 cell cultures used showed morphological heter ogeneity, consisting of at least two cellular subpopulations. This was reflected in the staining for E-cadherin, desmoglein and desmoplakins I & II, ATRA increased E-cadherin staining at cell-cell contact sites , but had no influence on the staining patterns of desmoglein and desm oplakins I Sr II, Similar to what has been observed for the cytoskelet al differentiation parameters, liarozole alone had no influence on E-c adherin, desmoglein or desmoplakins I & II expression, but in combinat ion with ATRA again intensified the effects on E-cadherin distribution . These effects on MCF-7 cells agree with previously obtained observat ions concerning the inhibition of ATRA catabolism by liarozole, Furthe rmore, our data support the hypothesis that the antiproliferative prop erties of the drug are accompanied by induction of differentiation.