Sodium butyrate and tributyrin induce in vivo growth inhibition and apoptosis in human prostate cancer.
Sodium butyrate and tributyrin induce in vivo growth inhibition and apoptosis in human prostate cancer.
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DOI：
10.1038/sj.bjc.6601510
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发表时间：
2004-01-26
影响因子：
8.8
通讯作者：
Gschwend, J E
中科院分区：
文献类型：
--
作者：
Kuefer, R;Hofer, M D;Altug, V;Zorn, C;Genze, F;Kunzi-Rapp, K;Hautmann, R E;Gschwend, J E
组蛋白去乙酰化酶抑制剂（HDAC）已知对多种癌细胞表现出抗增殖作用。在这项研究中，研究了两种HDAC，丁酸钠和三丁酸甘油酯对前列腺癌生长抑制的体内效率。为了深入了解可能的潜在途径，进行了细胞培养实验，重点是p21，Rb和c-myc的表达。对于体内试验，将前列腺癌细胞系（PC 3和TSU-Pr 1）接种在绒毛尿囊膜（CAM）上，并植入裸鼠异种移植模型中。对HDAC处理的与未处理的前列腺癌细胞中p21、Rb和c-myc的蛋白表达进行标准蛋白质印迹分析。丁酸钠和三丁酸甘油酯在已经非常低的0.1 mM浓度下对鸡蛋上的微肿瘤具有相当大的治疗效果。三丁酸甘油酯处理的肿瘤显示出最强的效果，在前列腺癌细胞系PC 3中具有38%的凋亡细胞核。在小鼠模型中，丁酸钠和三丁酸甘油酯之间几乎没有差异。在未治疗的动物中，肿瘤在植入后4周几乎是两倍大小。治疗组的肿瘤具有显著较低的Ki-67阳性染色细胞核百分比。Western blot分析表明，这些作用似乎与p53的状态无关，可能涉及通过p21-Rb-c-myc的途径。在这项研究中，我们已经证明了一个实质性的体内治疗效果，这可以通过在人前列腺癌中应用丁酸钠或口服三丁酸甘油酯来诱导。给出的结果可能提供了将这些药物应用于特定治疗后复发风险高的患者或局部或远处晚期前列腺癌患者的对照良好的临床试验的基本原理。
Histone deacetylase inhibitors (HDACs) are known to exhibit antiproliferative effects on various carcinoma cells. In this study, the in vivo efficiency of two HDACs, sodium butyrate and tributyrin, on prostate cancer growth inhibition were investigated. To gain an insight into the possible underlying pathways, cell culture experiments were performed focusing on the expression of p21, Rb and c-myc. For in vivo testing, prostate cancer cell lines (PC3 and TSU-Pr1) were seeded on the chorioallantois membrane (CAM) and implanted in a xenograft model using nude mice. Standard Western blot analysis was performed for protein expression of p21, Rb and c-myc in HDAC-treated vs untreated prostate cancer cells. Both sodium butyrate and tributyrin had a considerable treatment effect on microtumours on the chicken egg at already very low concentrations of 0.1 mM. Tributyrin-treated tumours showed the strongest effect with 38% apoptotic nuclei in the prostate cancer cell line PC3. In the mouse model, there was almost no difference between sodium butyrate and tributyrin. In untreated animals the tumours were almost double the size 4 weeks after implantation. Tumours of the treatment groups had a significantly lower percentage of Ki-67-positive-stained nuclei. As demonstrated by Western blot analysis, these effects seem to be independent of p53 status and a pathway via p21–Rb–c-myc is possibly involved. In this study we have demonstrated a substantial in vivo treatment effect, which can be induced by the application of sodium butyrate or the orally applicable tributyrin in human prostate cancer. The given results may provide the rationale to apply these drugs in well-controlled clinical trials in patients being at high risk of recurrence after specific therapy or in patients with locally or distant advanced prostate cancer.