Retinoid-related molecule AGN193198 potently induces G2M arrest and apoptosis in bladder cancer cells

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.