Antagonists of retinoic acid receptors (RARs) are potent growth inhibitors of prostate carcinoma cells

Abstract

Novel synthetic antagonists of retinoic acid receptors (RARs) have been developed. To avoid interference by serum retinoids when testing these compounds, we established serum-free grown sub-lines (>3 years) of the prostate carcinoma lines LNCaP, PC3 and DU145. A high affinity pan-RAR antagonist (AGN194310, Kd for binding to RARs = 2–5 nM) inhibited colony formation (by 50%) by all three lines at 16–34 nM, and led to a transient accumulation of flask-cultured cells in G1 followed by apoptosis. AGN194310 is 12–22 fold more potent than all-trans retinoic acid (ATRA) against cell lines and also more potent in inhibiting the growth of primary prostate carcinoma cells. PC3 and DU145 cells do not express RARβ, and an antagonist with predominant activity at RARβ and RARγ (AGN194431) inhibited colony formation at concentrations (∼100 nM) commensurate with a Kd value of 70 nM at RARγ. An RARα antagonist (AGN194301) was less potent (IC50 ∼200 nM), but was more active than specific agonists of RARα and of βγ. A component(s) of serum and of LNCaP-conditioned medium diminishes the activity of antagonists: this factor is not the most likely candidates IGF-1 and EGF. In vitro studies of RAR antagonists together with data from RAR-null mice lead to the hypothesis that RARγ-regulated gene transcription is necessary for the survival and maintenance of prostate epithelium. The increased potencies of RAR antagonists, as compared with agonists, suggest that antagonists may be useful in the treatment of prostate carcinoma. © 2001 Cancer Research Campaign http://www.bjcancer.com

An antagonist of retinoic acid receptors more effectively inhibits growth of human prostate cancer cells than normal prostate epithelium

“…When Lu et al (1999) screened more than 100 retinoids, three RARg agonists were the most active, but concentrations of 1 -10 mM were needed for complete growth inhibition. Similarly, we observed little effect of specific agonists of RARa and RARbg on colony formation by the above cell lines (Hammond et al, 2001). In clinical studies, 13-cis retinoic acid (isotretinoin) (with or without interferon-a) is only modestly effective against prostate carcinoma (DiPaolo and Aisner, 1999;Kelly et al, 2000;Shalev et al, 2000).…”

“…ATRA and synthetic retinoid receptor agonists are not very effective in inducing growth arrest and/or apoptosis in prostate cancer cell lines such as LNCaP, DU-145 and PC-3: high concentrations (B1 -10 mM) are generally needed (Gao et al, 1999;Hammond et al, 2001). When Lu et al (1999) screened more than 100 retinoids, three RARg agonists were the most active, but concentrations of 1 -10 mM were needed for complete growth inhibition.…”

“…For example, the pan-antagonist AGN194310 inhibits colony formation at around 50 nM -it is around 20-fold more potent than ATRA, and promotes growth arrest and apoptosis (Hammond et al, 2001). AGN194310 also inhibited the growth of primary prostate carcinoma cells from two patients more effectively than ATRA (Hammond et al, 2001).…”

Primary cell cultures as models of prostate cancer development

“…Somewhat surprisingly, antagonists of retinoic acid receptors were reportedly potent growth inhibitors of primary cultures of prostate cancer cells as well as of cancer cell lines (Hammond et al 2001). While no mechanistic explanation for this unexpected finding was presented, it is possible that this result relates to the apparent growth stimulatory effect of low concentrations of retinoic acid that have been observed in primary cultures of prostatic epithelial cells (Peehl et al 1993).…”

Nuclear orphan receptor TR3/Nur77 mediates melanoma cell apoptosis

“…49 In addition, other receptors, such as TR3, are also involved in the regulatory process of ATRA through formation of RXR/TR3 heterodimers. 24 A recent study shows that the cytotoxic effects of ATRA is mediated through mitochondrial dysfunction and induction of apoptosis.…”