The novel synthetic
retinoid-related molecule 4-[3-(1-heptyl-4,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-oxo-propenyl]
benzoic acid (
AGN193198) neither binds effectively to
retinoic acid receptors (RARs) and
retinoid X receptors (RXRs) nor transactivates in RAR- and RXR-mediated reporter assays. Even so,
AGN193198 is potent in inducing apoptosis in human prostate and
breast carcinoma cells (Keedwell et al.,
Cancer Res 2004;64:3302-12). Here, we extend these findings to show that
AGN193198 potently and rapidly induces apoptosis in bladder
carcinoma cell lines. One micromolar of
AGN193198 completely abolished the growth of the
transitional cell carcinoma lines UM-UC-3 and J82, and the
squamous cell carcinoma line SCaBER; the transitional cell
papilloma line RT-4 was slightly less sensitive to the growth inhibitory effect of
AGN193198. Treated cells accumulated in the G2M phase of the cell cycle. This was accompanied by apoptosis, as revealed by staining cells for exposure of
phosphatidylserine at their surface (binding of
Annexin V) and FACS analysis of
propidium iodide labeled cells. As reported for
prostate cancer cells,
AGN193198 provoked rapid activation of caspases-3 (by 6 hr), -8 (by 16 hr) and -9 (by 6 hr) in
bladder cancer cells. These findings suggest that
AGN193198 and related compounds, whose mechanism of action does not appear to involve RARs and RXRs, may be useful in the treatment of
bladder cancer.