Four candidate
retinoid antagonists (
LE135,
LE511,
LE540, and
LE550) were designed on the basis of the
ligand superfamily concept and synthesized. Analysis of these related
retinoids by transient transfection assay demonstrated that
LE135,
LE540, and
LE550 are effective
retinoic acid receptor (RAR) antagonists, whereas
LE511 selectively induced RARbeta transcriptional activity. Both
LE135 and
LE540 inhibited
retinoic acid (RA)-induced transcriptional activation of RARbeta, but not RARalpha, RARgamma or
retinoid X receptor alpha (RXRalpha), on a variety of RA response elements. The
retinoid antagonists also inhibited all-trans-RA-induced transcriptional activation of RARbeta/RXRalpha heterodimers, although they did not show any effect on transactivation activity of RXR/RXR homodimers. In ZR-75-1 human
breast cancer cells, cotreatment of
LE135 and
LE540 with all-trans-RA inhibited all-trans-RA-induced apoptosis of the cells, further demonstrating that RARbeta plays a role in RA-induced apoptosis of
breast cancer cells. We also evaluated the effect of these
retinoids on
AP-1 activity. Our data showed that
LE135 and
LE540 strongly repressed 12-O-tetradecanoylphorbol-13-acetate-induced
AP-1 activity in the presence of RARbeta and RXRalpha. Interestingly,
LE550 induced
AP-1 activity when RARbeta and RXRalpha were expressed in HeLa cells but not in
breast cancer cells. These results demonstrate that
LE135 and
LE540 were a novel class of RARbeta-selective antagonists and anti-AP-1
retinoids and should be useful tools for studying the role of
retinoids and their receptors.