Phenylbutyrate and phenylacetate induce differentiation and inhibit proliferation of human medulloblastoma cells
Phenylbutyrate and phenylacetate induce differentiation and inhibit proliferation of human medulloblastoma cells
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DOI：
10.1158/1078-0432.ccr-0747-3
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发表时间：
2004-02-01
影响因子：
11.5
通讯作者：
Lau, CC
中科院分区：
文献类型：
--
作者：
Li, XN;Parikh, S;Lau, CC
目的：苯丁酸酯(PB)和苯乙酸酯(PA)在恶性肿瘤中具有抗增殖和诱导分化作用，已在I/II期临床试验中得到评价。本研究旨在评价它们在髓母细胞瘤中的抗肿瘤活性。实验设计：通过体外和体内长期的形态、增殖、分化、非贴壁生长、细胞凋亡和致瘤性实验，研究了0.1~3 mM的PB和PA对两种髓母细胞瘤细胞株DAOY和D283-MED的生物学效应。结果：PB和PA均能诱导细胞形态的改变，并抑制细胞增殖，且呈时间和剂量依赖性。这些影响在PB中更为明显，在D283-MED细胞中，在连续暴露于3 mMPB 28天后，这些效应变得不可逆。PB和PA均能增加胶质细胞标记物胶质纤维酸性蛋白和神经元标记物突触素的表达。在D283-MED细胞中，PB比PA对锚定非依赖性生长的抑制作用更明显。与DAOY细胞相比，PB对D283-MED细胞的细胞周期停滞作用更明显，致瘤性显著降低。低剂量PB或短期处理均可诱导D283-MED细胞发生凋亡。相比之下，需要更高浓度的PB或更长时间的处理才能达到与DAOY细胞类似的效果。PB诱导组蛋白H3乙酰化，而组蛋白H4乙酰化仅见于D283-MED细胞。结论：PB通过诱导组蛋白H3和H4乙酰化，是一种比PA更有效的抗肿瘤药物。283-MED细胞对PB的敏感性高于DAOY细胞，这可能与其原始分化状态以及组蛋白H4乙酰化状态的变化有关。
Purpose: Phenylbutyrate (PB) and phenylacetate (PA) have antiproliferative and differentiation-inducing effects in malignant tumors, and had been evaluated in Phase I/II clinical trials. This study was undertaken to evaluate their antitumor activities in medulloblastomas.Experimental Design: The biological effects of PB and PA, ranging from 0.1 mm to 3 mm, on two medulloblastoma cell lines (DAOY and D283-MED) were examined using various long-term in vitro and in vivo assays for morphology, proliferation, differentiation, anchorage-independent growth, apoptosis, and tumorigenicity.Results: PB and PA can both induce morphological changes and suppress proliferation in a time- and dose-dependent manner. These effects were more pronounced with PB and became irreversible in D283-MED cells after continuous exposure to 3 mm PB for 28 days. Both PB and PA were able to increase expression of glial marker glial fibriliary acidic protein and neuronal marker synaptophysin in two cell lines. For anchorage-independent growth, PB showed a more significant suppression than PA in D283-MED cells. PB caused more pronounced cell cycle arrest and remarkably reduced tumorigenicity in D283-MED cells than in DAOY cells. Apoptosis was readily induced in D283-MED cells with either low dose of PB or short-term treatment. In contrast, much higher concentrations of PB or longer treatment were required to achieve similar effect with DAOY cells. PB induced increased histones H3 acetylation in both cell lines, but histone H4 acetylation was only observed in D283-MED cells.Conclusions: PB, through induction of hyperacetylation of histone H3 and H4, is a much more potent antitumor agent than PA. 283-MED cells are more responsive to PB than DAOY cells, which may be dependent on their original state of differentiation as well as the changes of histone H4 acetylation status.