Antagonists of retinoic acid receptors (RARs) are potent growth inhibitors of prostate carcinoma cells.
Antagonists of retinoic acid receptors (RARs) are potent growth inhibitors of prostate carcinoma cells.
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DOI：
10.1054/bjoc.2001.1939
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发表时间：
2001-08-03
影响因子：
8.8
通讯作者：
Brown, G
中科院分区：
文献类型：
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作者：
Hammond, L A;Van Krinks, C H;Durham, J;Tomkins, S E;Burnett, R D;Jones, E L;Chandraratna, R A;Brown, G
已开发出新型合成的视黄酸受体（RAR）拮抗剂。为了避免在测试这些化合物时血清类维生素A的干扰，我们建立了前列腺癌细胞系LNCaP、PC 3和DU 145的无血清生长亚系（>3年）。高亲和力的pan-RAR拮抗剂（AGN 194310，与RAR结合的Kd = 2-5 nM）在16-34 nM下抑制所有三种细胞系的集落形成（50%），并导致G1中培养瓶培养的细胞的瞬时积累，随后细胞凋亡。 AGN 194310比全反式维甲酸（ATRA）对细胞系的效力高12-22倍，并且在抑制原发性前列腺癌细胞的生长方面也更有效。PC 3和DU 145细胞不表达RARβ，在RARβ和RARγ具有主要活性的拮抗剂（AGN 194431）在与RARγ的Kd值70 nM相当的浓度（> 100 nM）下抑制集落形成。 RARα拮抗剂（AGN 194301）的效力较低（IC 50 <200 nM），但比RARα和βγ的特异性激动剂更有效。 血清和LNCaP条件培养基的组分降低拮抗剂的活性：该因子不是最可能的候选物IGF-1和EGF。RAR拮抗剂的体外研究以及来自RAR缺失小鼠的数据导致了RARγ调节的基因转录对于前列腺上皮的存活和维持是必需的这一假设。与激动剂相比，RAR拮抗剂的效力增加，表明拮抗剂可用于治疗前列腺癌。© 2001年癌症研究运动http://www.bjcancer.com
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