4-Hydroxyphenyl Retinamide Is a Highly Selective Activator of Retinoid Receptors

Abstract

Retinoids have shown promise as anti-cancer and cancer preventative agents. All-trans-N-(4-hydroxyphenyl)-retinamide (4HPR) belongs to a new group of retinoids that not only inhibit the proliferation of cancer cells but also can induce apoptosis in certain cancer cells. Because of its increased efficacy against cancer cells and its low toxicity it has been entered into a number of clinical trials. However, its mechanism of action is not known, and it had been assumed that it is not a true retinoid. Here we analyze its ability to function as an activator of nuclear retinoid receptors (RARs and RXRs). We observe that, in transactivation assays, 4HPR is a potent transactivator with RAR␥ and a moderate activator with RAR␤ but is not an activator with RAR␣ and RXR␣. Furthermore, RAR␥-selective transactivation by 4HPR is enhanced on some response elements and reduced on others when compared to natural retinoids. In contrast to transactivation, 4HPR in transrepression assays functions mostly with RAR␣, RAR␤, and RXR␣. Optimal receptor activation is seen at 4HPR concentrations at which it is a potent growth inhibitor and inducer of apoptosis. We conclude that 4HPR is a highly selective activator of retinoid receptors. We propose that this selective activation of the nuclear receptors is likely to be the basis for its specific biological activities and its favorable pharmaceutical properties.

Effects of retinoic acid and fenretinide on the c-erbB-2 expression, growth and cisplatin sensitivity of breast cancer cells

“…Two different mechanisms of retinoid action are known. Interaction with RARs/RXRs induces wansactivation of responsive genes and/or inhibition of the AP-1 transcription factor (Fanjul et al, 1994(Fanjul et al, , 1996. Retinoid receptors act as liganddependent transcription factors and reveal striking homologies to the steroid receptors.…”

“…Compared with ATRA. 4-HPR reveals differential and weaker RARIRXR transactivation (Fanjul et al, 1996). which might explain its low hepatotoxicity.…”

“…In addition. both retinoids inhibit the AP-1 transcription factor (Fanjul et al, 1994(Fanjul et al, , 1996, which becomes activated upon growth factor signalling. Therefore, a negative interaction between retinoid and growth factor signalling seems to occur. Progression of carcinomas has been linked to the expression of oncogenes, such as c-mvc and c-erbB-2 (also referred to as HER-2 or neu) (Somay et al 1992;Grunt et al 1995).…”

pRb and Cdk regulation by N-(4-hydroxyphenyl)retinamide

“…Accordingly, while apoptosis by HPR appears receptor-independent (Delia et al, 1993;Kitareewan et al, 1999), and actually correlates with the ability of HPR to elicit intracellular free radicals and acidi®cation (Delia et al, 1997a;Angoli et al, 1996;Maurer et al, 1999;Suzuki et al, 1999), transcriptional regulation of target genes (e.g. AP1) is retinoid-receptor dependent, according to data showing that HPR selectively activates the transcription by RAR-g, to a less extent by RAR-b, but not by RAR-a (Fanjul et al, 1996;Kazmi et al, 1996).…”

Solid phase-assisted synthesis and screening of a small library of N-(4-hydroxyphenyl)retinamide (4-HPR) analogs

“…The receptors function as ligand-dependent transcription factors 9 and some researchers have reported that 4-HPR can activate RARs in transactivation assays. 10 We and others find, however, that 4-HPR has low affinity for the retinoid receptors. 11-13 4-HPR has also been shown to induce apoptosis in both atRA -sensitive and -resistant cells, pointing to a mode of action that is independent of the RAR.…”