Synthetic
retinoid-related molecules, such as
N-(4-hydroxyphenyl)retinamide (
fenretinide) and 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-
naphthalene carboxylic acid (CD437) induce apoptosis in a variety of malignant cells. The mechanism(s) of action of these compounds does not appear to involve
retinoic acid receptors (RARs) and
retinoid X receptors (RXRs), although some investigators disagree with this view. To clarify whether some
retinoid-related molecules can induce apoptosis without involving RARs and/or RXRs, we used 4-[3-(1-heptyl-4,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-oxo-E-propenyl]
benzoic acid (
AGN193198) that neither binds effectively to RARs and RXRs nor transactivates in RAR- and RXR-mediated reporter assays.
AGN193198 potently induced apoptosis in prostate, breast, and gastrointestinal
carcinoma cells and in
leukemia cells.
AGN193198 also abolished growth (by 50%
at 130-332 nM) and induced apoptosis in primary cultures established from prostatic
carcinoma (13 patients) and gastrointestinal
carcinoma (1 patient). Apoptosis was induced rapidly, as indicated by mitochondrial depolarization and DNA fragmentation. Molecular events provoked by
AGN193198 included activation of
caspase-3, -8, -9, and -10 (by 4-6 h) and the production of BID/p15 (by 6 h). These findings show that
caspase-mediated induction of apoptosis by
AGN193198 is RAR/RXR-independent and suggest that this compound may be useful in the treatment of
prostate cancer.