Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses the growth of prostate cancer cells in vitro and in vivo.
Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses the growth of prostate cancer cells in vitro and in vivo.
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发表时间：
2000-09
期刊：
影响因子：
11.2
通讯作者：
L. Butler;D. Agus;H. Scher;B. Higgins;Adam Rose;C. Cordon-Cardo;H. Thaler;R. Rifkind;PA Marks-PA
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作者：
L. Butler;D. Agus;H. Scher;B. Higgins;Adam Rose;C. Cordon-Cardo;H. Thaler;R. Rifkind;PA Marks-PA
辛二酰苯胺异羟肟酸（SAHA）是一个混合极性化合物家族的原型，其诱导转化细胞的生长停滞，并显示出治疗癌症的前景。SAHA诱导培养物中某些转化细胞的分化和/或凋亡，并且是组蛋白脱乙酰酶的有效抑制剂。在这项研究中，我们研究了SAHA对培养的人前列腺癌细胞的生长和对裸鼠体内CWR 22人前列腺异种移植物生长的影响。SAHA在微摩尔浓度（2.5-7.5 μ M）下抑制LNCaP、PC-3和TSU-Pr 1细胞系的生长。SAHA在LNCaP细胞中诱导剂量依赖性细胞死亡。在移植了CWR 222人前列腺肿瘤的小鼠中，与仅接受溶媒的小鼠相比，SAHA（25、50和100 mg/kg/天）可显著抑制肿瘤生长;与对照组相比，50 mg/kg/天给药导致平均最终肿瘤体积减少97%。在该剂量下，通过体重增加和尸检检查评价，未检测到毒性。在SAHA给药后6小时内，在CWR 22肿瘤中检测到乙酰化核心组蛋白的积累增加。SAHA诱导CWR 22前列腺癌细胞中前列腺特异性抗原mRNA表达，导致血清前列腺特异性抗原水平高于仅从肿瘤体积预测的水平。结果表明，基于异羟肟酸的混合极性化合物抑制前列腺癌细胞生长，并且可能是用于治疗前列腺癌的有用的、相对无毒的药剂。
Suberoylanilide hydroxamic acid (SAHA) is the prototype of a family of hybrid polar compounds that induce growth arrest in transformed cells and show promise for the treatment of cancer. SAHA induces differentiation and/or apoptosis in certain transformed cells in culture and is a potent inhibitor of histone deacetylases. In this study, we examined the effects of SAHA on the growth of human prostate cancer cells in culture and on the growth of the CWR22 human prostate xenograft in nude mice. SAHA suppressed the growth of the LNCaP, PC-3, and TSU-Pr1 cell lines at micromolar concentrations (2.5-7.5 microM). SAHA induced dose-dependent cell death in the LNCaP cells. In mice with transplanted CWR222 human prostate tumors, SAHA (25, 50, and 100 mg/kg/day) caused significant suppression of tumor growth compared with mice receiving vehicle alone; treatment with 50 mg/kg/day resulted in a 97% reduction in the mean final tumor volume compared with controls. At this dose, there was no detectable toxicity as evaluated by weight gain and necropsy examination. Increased accumulation of acetylated core histones was detected in the CWR22 tumors within 6 h of SAHA administration. SAHA induced prostate-specific antigen mRNA expression in CWR22 prostate cancer cells, resulting in higher levels of serum prostate-specific antigen than predicted from tumor volume alone. The results suggest that hydroxamic acid-based hybrid polar compounds inhibit prostate cancer cell growth and may be useful, relatively nontoxic agents for the treatment of prostate carcinoma.