Butler L M, Agus D B, Scher H I, Higgins B, Rose A, Cordon-Cardo C, Thaler H T, Rifkind R A, Marks P A, Richon V M
Cell Biology Program Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Cancer Res. 2000 Sep 15;60(18):5165-70.
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.
伏立诺他（SAHA）是一类杂化极性化合物的原型，这类化合物可诱导转化细胞生长停滞，在癌症治疗方面显示出前景。SAHA可诱导培养中的某些转化细胞分化和/或凋亡，是一种有效的组蛋白脱乙酰酶抑制剂。在本研究中，我们检测了SAHA对培养的人前列腺癌细胞生长以及对裸鼠体内CWR22人前列腺异种移植瘤生长的影响。SAHA在微摩尔浓度（2.5 - 7.5 microM）时可抑制LNCaP、PC - 3和TSU - Pr1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CWR22人前列腺肿瘤的小鼠中，与单独接受赋形剂的小鼠相比，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/天的治疗导致平均最终肿瘤体积减少97%。在此剂量下，通过体重增加和尸检评估未检测到毒性。在SAHA给药后6小时内，在CWR22肿瘤中检测到乙酰化核心组蛋白的积累增加。SAHA在CWR22前列腺癌细胞中诱导前列腺特异性抗原mRNA表达，导致血清前列腺特异性抗原水平高于仅由肿瘤体积预测的水平。结果表明，基于异羟肟酸的杂化极性化合物可抑制前列腺癌细胞生长，可能是治疗前列腺癌的有用且相对无毒的药物。
