Inhibitory effects of nordihydroguaiaretic acid (NDGA) on the IGF-1 receptor and androgen dependent growth of LAPC-4 prostate cancer cells.
Inhibitory effects of nordihydroguaiaretic acid (NDGA) on the IGF-1 receptor and androgen dependent growth of LAPC-4 prostate cancer cells.
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DOI：
10.1002/pros.20789
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发表时间：
2008-08-01
期刊：
影响因子：
--
通讯作者：
Goldfine ID
中科院分区：
文献类型：
--
作者：
Ryan CJ;Zavodovskaya M;Youngren JF;Campbell M;Diamond M;Jones J;Shiry L;Allan G;Maddux BA;Goldfine ID
去甲二氢愈创木酸（NDGA）是乳腺癌和其他癌症中IGF-1受体（IGF-1 R）的抑制剂，并伴随抑制培养细胞和动物中的肿瘤生长。目前的研究评估NDGA对雄激素刺激的人前列腺癌细胞生长的影响。将组织培养物中的LAPC-4前列腺癌细胞雄激素饥饿3天，然后加入InM二氢睾酮（DHT）和其他雄激素长达7天，并测量细胞增殖。免疫印迹法检测IGF-1 R蛋白表达，定量PCR法检测IGF-1 R mRNA表达。通过ELISA测量IGF-1 R受体激酶活化。7天后，LAPC-4生长通过InM DHT加倍。NDGA对IGF-1诱导的IGF-1 R自身磷酸化有快速的抑制作用。DHT可增加IGF-1 R蛋白和mRNA的表达。在添加雄激素后3天观察到最大IGF-1 R蛋白水平。此外，NDGA在10 μM或更低浓度下，抑制了生长在平板中的细胞和生长在软琼脂中的细胞中的DHT诱导的增殖。雄激素受体（AR）的FRET研究表明，NDGA没有响应配体对AR的构象影响。NDGA通过多种机制阻断DHT诱导的LAPC-4前列腺癌细胞生长，包括快速抑制IGF-1 R激酶和剂量依赖性抑制雄激素刺激IGF-1 R表达。该药物的临床研究将确定其在雄激素依赖性前列腺癌中的疗效。
Nordihydroguaiaretic acid (NDGA) is an inhibitor of the IGF-1 receptor (IGF-1R) in breast and other cancers, and concomitantly inhibits tumor growth both in cultured cells and animals. The current study evaluates the effect of NDGA on the androgen-stimulated growth of human prostate cancer cells. LAPC-4 prostate cancer cells in tissue culture were androgen starved for 3 days, 1 nM dihydrotestosterone (DHT) and other androgens were then added for up to 7 days, and cell proliferation measured. IGF-1R protein expression was measured by western blot, and IGF-1R mRNA expression by quantitative PCR. IGF-1R receptor kinase activation was measured by ELISA. After 7 days, LAPC-4 growth was doubled by 1 nM DHT. NDGA had a rapid effect to inhibit IGF-1R autophosphorylation induced by IGF-1. DHT increased the expression of IGF-1R protein and mRNA levels. Maximal IGF-1R protein levels were observed 3 days after the addition of androgen. In addition, NDGA, at 10 μM or less, inhibited DHT-induced proliferation in both cells grown in plates and cells grown in soft agar. Androgen receptor (AR) studies by FRET revealed that NDGA had no conformational effects on the AR in response to ligand. NDGA blocks the DHT-induced growth of LAPC-4 prostate cancer cells by several mechanisms including rapid inhibition of the IGF-1R kinase, and a dose-dependent inhibition of androgen stimulation of IGF-1R expression. Clinical studies of this agent will determine its efficacy in the setting of androgen-dependent prostate cancer.
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影响因子：
56.9
作者：
Chan, JM;Stampfer, MJ;Pollak, M
通讯作者：
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影响因子：
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作者：
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影响因子：
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作者：
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影响因子：
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作者：
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影响因子：
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作者：
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通讯作者：
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