A new class of retinoids with selective inhibition of AP-1 inhibits proliferation

Abstract

Retinoids regulate many biological processes, including differentiation, morphogenesis and cell proliferation. They are also important therapeutic agents, but their clinical usefulness is limited because of side effects. Retinoid activities are mediated by specific nuclear receptors, the RARs and RXRs, which can induce transcriptional activation through specific DNA sites or by inhibiting the transcription factor AP-1 (refs 12-15), which usually mediates cell proliferation signals. Because the two types of receptor actions are mechanistically distinct, we investigated whether conformationally restricted retinoids, selective for each type of receptor action, could be identified. Here we describe a new class of retinoids that selectively inhibits AP-1 activity but does not activate transcription. These retinoids do not induce differentiation in F9 cells but inhibit effectively the proliferation of several tumour cell lines, and could thus serve as candidates for new retinoid therapeutic agents with reduced side effects.

Tumor promoter-induced ornithine decarboxylase gene expression occurs independently of AP-1 activation

“…Both ODC (Love et al, 1998;Carbone et al, 1998) and AP-1 (Fanjul et al, 1994) have been chosen as potential targets for chemoprevention in clinical trials. The understanding of how two important chemoprevention targets, ODC and AP-1, interact with each other is important in the possible future understanding and development of strategies for rational prevention of cancer.…”

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.…”

“…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).…”

Retinoids arrest breast cancer cell proliferation: retinoic acid selectively reduces the duration of receptor tyrosine kinase signaling

“…The ability of retinoids to inhibit the proliferation of tumor cells, or to prevent de novo transformation of normal cells, correlates with their ability to inhibit the transcription factor AP1 [9,[13][14][15][16][17][18][19][20][21]35,36]. Several mechanisms have been proposed to account for the anti-AP1 activity of retinoids.…”

“…The ability of RA to regulate cell proliferation is associated with the ability of ligand-bound RARs to interfere with the function of the mitogenic transcription factor, AP1 [9,[13][14][15][16][17][18][19]. Although in some circumstances retinoid inhibition of AP-1 function is independent of the transcriptional activity of RARs, in many other situations it is associated with retinoid-induced changes in expression of components of cellular signaling pathways [20][21][22][23].…”