Retinoids are natural and synthetic derivatives of
vitamin A that have great promise for
cancer therapy and
chemoprevention. Of the
retinoids developed so far, 4-(N-hydroxyphenyl)retinamide (4-HPR or
fenretinide) appears to have the best therapeutic potential in vitro and in vivo and is currently being tested in clinical trials for
cancer prevention and
therapy. To develop other potentially potent
antitumor agents, we synthesized 85
retinoid derivatives. In an initial screening of these synthetic
retinoids using the HCT116
colon cancer cell line, we found that
4-amino-2-(butyrylamino)phenyl(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexenyl)-2,4,6,8-nonatetraenoate (ABPN or CBG41) induced the greatest growth inhibition, with an IC(50) value of 0.6 microM. Subsequent studies in other
cancer cell lines indicated that ABPN was much more growth-inhibitory than
all-trans retinoic acid or
4-HPR. Compared to
4-HPR, ABPN induced 5.5- to 70.0-fold more growth inhibition in most
cancer cells, with the exception of gynecologic
cancer cells. In these cells, the antiproliferative effect was only 1.5- to 2.8-fold more than
4-HPR. We examined the molecular mechanism underlying the difference in growth inhibition between
4-HPR and ABPN.
DAPI staining, DNA fragmentation, FACS and Western blotting analyses suggest that ABPN induced apoptosis by activating
caspase-3 and -8, which may result in increased PARP cleavage. Unlike
4-HPR, ABPN activated all 3 RAR isotypes to an extent similar to AtRA. In addition, ABPN significantly inhibited
AP-1 transcriptional activity and thus greatly suppressed the expression of the
matrix metalloproteinase -1, -2 and -3 genes, which are involved in
tumor invasion. These results suggest that ABPN may be a promising
retinoid derivative offering not only enhanced cytotoxicity, but also increased inhibition of
tumor invasiveness.