Apoptosis induction in cancer cells by a novel analogue of 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid lacking retinoid receptortranscriptional activation activity

The retinoid 6-[3-(1 -adamantyl)-3-hydroxyphenyl]-2-naphthale boxylic acid (AHPN) is reported to have anticancer activity in vivo. Induction of cell c ycle arrest and apoptosis in cancer cell lines refractory to standard retin oids suggests a retinoid-independent mechanism of action for AHPN. Conforma tional studies suggested that binding of AHPN does not induce an unusual co nformation in retinoic acid receptor (RAR) gamma, The 3-chloro AHPN analogu e MM11453 inhibited the growth of both retinoid-resistant (HL-60R leukemia, MDA-MB-231 breast, and H292 lung) and retinoid-sensitive (MCF-7 breast, LN CaP prostate, and H460 lung) cancer cell lines by inducing apoptosis at sim ilar concentrations. Before apoptosis, MM11453 induced transcription factor TR3 expression and loss of mitochondrial membrane potential characteristic of apoptosis, MM11453 lacked the ability to significantly activate RARs an d retinoid X receptor ru to initiate (TREpal)(2)-tk-CAT reporter transcript ion. These results, differential proteolysis-sensitivity assays, and glutat hione S-transferase-pulidown experiments demonstrate that, unlike AHPN or t he natural or standard synthetic retinoids, MM11453 does not behave as a RA R or retinoid X receptor alpha transcriptional agonist, These studies stron gly suggest that AHPN exerts its cell cycle arrest and apoptotic activity b y a signaling pathway independent of retinoid receptor activation.