Liarozole potentiates the all-trans-retinoic acid-induced structural remodelling 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, liarozole 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 cytokeratins 8, 18, and 19, actin, E-cadherin, desmoglein and desmoplakins I & II. ATRA concentration-dependently (10(-8) M-10(-6) M) induced changes in actin stress fibers and cytokeratin intermediate filaments. These changes were accompanied by a more obvious interaction of these filaments with junctional complexes. Surface area and volume of the MCF-7 cells increased markedly after ATRA exposure, with extensive filopodia formation. Liarozole (10(-6) M) alone had no effect on cell morphology, cytokeratin or actin organization, or on cellular junctions. In combination with ATRA (10(-9) M and 10(-8) M), liarozole potentiated the ATRA-induced effects. The MCF-7 cell cultures used showed morphological heterogeneity, 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 desmoplakins I & II. Similar to what has been observed for the cytoskeletal differentiation parameters, liarozole alone had no influence on E-cadherin, desmoglein or desmoplakins I & II expression, but in combination with ATRA again intensified the effects on E-cadherin distribution. These effects on MCF-7 cells agree with previously obtained observations concerning the inhibition of ATRA catabolism by liarozole. Furthermore, our data support the hypothesis that the antiproliferative properties of the drug are accompanied by induction of differentiation.
Van heusden
J
J
Department of Molecular Cell Biology & Genetics, University of Limburg, Maastricht, The Netherlands.
Borgers
M
M
Ramaekers
F
F
Xhonneux
B
B
Wouters
W
W
De Coster
R
R
Smets
G
G
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000737:chemistry / Q000648:ultrastructure*; D002277:Carcinoma / Q000737:chemistry / Q000648:ultrastructure*; D015815:Cell Adhesion Molecules / Q000302:isolation & purification; D002455:Cell Division / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000302:isolation & purification; D003599:Cytoskeleton / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000302:isolation & purification; D014212:Tretinoin / Q000494:pharmacology*
D018931:Antineoplastic Agents, Hormonal; D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; D007093:Imidazoles; D009363:Neoplasm Proteins; D014212:Tretinoin; C061121:liarozole