Belinostat (PXD101) is a novel hydroxamate-type inhibitor of histone deacetylase (HDAC) activity in HeLa cell extracts with an IC50 of 27 nM [1].
Belinostat(1-5 μM)for 48 h caused a dose-dependent inhibition of proliferation, with the most potent inhibitory effect occurring on 5637 cells (IC50 of 1.0 μM), and the least effect occurring on RT4 cells (IC50 of 10.0 μM). T24 and J82 cell lines had an IC50 of 3.5 and 6.0 μM, respectively [2]. Belinostat inhibited the proliferation of human bladder cancer T24 cells with IC50 of 3.5μM [3].
Belinostat (10-40 mg/kg/day i.p.) daily for 7 days causes a significant dose-dependent growth delay with no obvious signs of toxicity to the colon tumor xenografts mice [1]. Gene expression analysis of belinostat-treated mice showed increased p21WAF1 gene transcript expression [3]. Belinostat monotherapy induced dose-proportional antitumor effects. When administered at 100 mg/kg, belinostat inhibited tumor size by 47% at day 15 on human ovarian cancer xenografts [4].
参考文献:
[1]. Plumb J A, Finn P W, Williams R J, et al. Pharmacodynamic response and inhibition of growth of human tumor xenografts by the novel histone deacetylase inhibitor PXD101[J]. Molecular cancer therapeutics, 2003, 2(8): 721-728.
[2]. Buckley M T, Yoon J, Yee H, et al. The histone deacetylase inhibitor belinostat (PXD101) suppresses bladder cancer cell growth in vitro and in vivo[J]. Journal of Translational Medicine, 2007, 5(1): 1-12.
[3]. Buckley M T, Yoon J, Yee H, et al. The histone deacetylase inhibitor belinostat (PXD101) suppresses bladder cancer cell growth in vitro and in vivo[J]. Journal of Translational Medicine, 2007, 5(1): 1-12.
[4]. Qian X, LaRochelle W J, Ara G, et al. Activity of PXD101, a histone deacetylase inhibitor, in preclinical ovarian cancer studies[J]. Molecular cancer therapeutics, 2006, 5(8): 2086-2095.
Belinostat (PXD101) 是 HeLa 细胞提取物中组蛋白脱乙酰酶 (HDAC) 活性的新型异羟肟酸型抑制剂，IC50 为 27 nM [1]。
Belinostat(1-5 μM) 48 h 引起剂量依赖性增殖抑制，对 5637 细胞的抑制作用最强（IC50 为 1.0 μM），对 RT4 细胞的作用最小（IC50 为10.0 μM）。 T24 和 J82 细胞系的 IC50 分别为 3.5 和 6.0 μM [2]。 Belinostat抑制人膀胱癌T24细胞增殖，IC50为3.5μM [3]。
Belinostat（10-40 mg/kg/天 i.p.）每天持续 7 天会导致显着的剂量依赖性生长延迟，而对结肠肿瘤异种移植小鼠没有明显的毒性迹象[1]。 belinostat 治疗小鼠的基因表达分析显示 p21WAF1 基因转录物表达增加[3]。 Belinostat 单一疗法诱导剂量成比例的抗肿瘤作用。当以 100 mg/kg 的剂量给药时，belinostat 在第 15 天时抑制了人卵巢癌异种移植物肿瘤大小的 47% [4]。
| Kinase experiment [1]: | |
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Preparation Method |
Reaction was carried out in a total volume of 150 μl of buffer [60 mm Tris (pH 7.4) containing 30% glycerol] containing 2 μl of cell extract and, where used, 2 μl of Belinostat. The reaction was started by the addition of 2 μl of [3H] labeled substrate (acetylated histone H4 peptide corresponding to the 20 NH2-terminal residues). Samples were incubated at 37°C for 45 min, and the reaction stopped by the addition of HCl and acetic acid (0.72 and 0.12 m final concentrations, respectively). |
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Reaction Conditions |
2 μl of Belinostat, incubated at 37°C for 45 min |
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Applications |
Belinostat inhibited histone deacetylase activity in cell lysates with an IC50 in the range 9–100 nM? |
| Cell experiment [1]: | |
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Cell lines |
The human ovarian cell line A2780, cisplatin (A2780/cp70) and doxorubicin (2780AD) resistant derivatives |
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Preparation Method |
Cells were plated in 5 ml of medium at a density of 8 × 104 cells/25 cm2 flask and allowed to attach and grow for 48 h. Cells were exposed to Belinostat (five concentrations from 0.016 to 10 μm) for 24 h. |
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Reaction Conditions |
0.016 to 10 μm, for 24 h |
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Applications |
Belinostat inhibited the growth of a number of human tumor cell lines with IC50s determined by a clonogenic assay in the range 0.2–3.4 μm? |
| Animal experiment [2]: | |
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Animal models |
female CD-1 athymic nude mice |
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Preparation Method |
Once tumors became established (～100 mm3 in size), animals were randomized (10 animals/group) and drug treatments were initiated. Belinostat was given by i.p. injection once daily for 15 consecutive days. Belinostat was prepared as a 50 mg/mL stock in Belinostat vehicle (pH ～9.4) and for administration was diluted in Belinostat vehicle to 10 mg/mL (for 100 mg/kg dose) |
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Dosage form |
i.p , 20, 40, 100 mg/kg, for 15 d. |
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Applications |
Belinostat monotherapy induced dose-proportional antitumor effects. When administered at 100 mg/kg, Belinostat inhibited tumor size by 47% at day 15 relative to vehicle-treated control animals. |
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参考文献: [1]. Plumb J A, Finn P W, Williams R J, et al. Pharmacodynamic response and inhibition of growth of human tumor xenografts by the novel histone deacetylase inhibitor PXD101[J]. Molecular cancer therapeutics, 2003, 2(8): 721-728. [2]. Qian X, LaRochelle W J, Ara G, et al. Activity of PXD101, a histone deacetylase inhibitor, in preclinical ovarian cancer studies[J]. Molecular cancer therapeutics, 2006, 5(8): 2086-2095. |
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