Radiation-induced enteropathy: Molecular basis of pentoxifylline-vitamin E anti-fibrotic effect involved TGF-β1 cascade inhibition
Radiation-induced enteropathy: Molecular basis of pentoxifylline-vitamin E anti-fibrotic effect involved TGF-β1 cascade inhibition
复制标题
DOI：
10.1016/j.radonc.2012.08.023
复制
发表时间：
2012-12-01
影响因子：
5.7
通讯作者：
Delanian, Sylvie
中科院分区：
文献类型：
--
作者：
Hamama, Saad;Gilbert-Sirieix, Marie;Delanian, Sylvie
背景：放射引起的纤维化是放射治疗的严重晚期并发症。己酮可可碱-维生素E在治疗纤维化方面已被临床试验证明有效且安全，但其活性的分子机制尚未探索。 方法：以SOMA评分为主要终点，采用己酮可可碱-维生素E联合治疗10例放射性肠病患者。同时，将从患有放射性肠病的人的肠样本中分离出的原代平滑肌细胞与己酮可可碱、曲洛克（维生素E亲水类似物）或其组合一起孵育。随后使用 Q-RT-PCR、基因报告仪、蛋白质印迹、ELISA 和免疫组织化学研究 TGF-β 1/Smad 和 Rho/ROCK 通路的激活。结果：己酮可可碱-维生素 E 组合在 6 个月和 18 个月时诱导症状消退 (SOMA) 分别为 41% 和 80%。在体外，己酮可可碱和 trolox 协同抑制 TGF-β1 蛋白和 mRNA 表达。这种抑制作用是在转录水平介导的，并导致随后抑制 TGF-β 1/Smad 靶标（Col I α 1、FN1、PAI-1、CTGF），而对 Rho/ROCK 通路没有影响。结论：己酮可可碱-维生素 E 组合的抗纤维化作用至少部分是通过抑制 TGF-β 1 级联介导的。它强化了先前显示己酮可可碱-维生素 E 协同作用的临床数据，并支持其用作放射诱导纤维化的一线治疗。 (C) 2012 Elsevier Ireland Ltd. 保留所有权利。放射治疗和肿瘤学105（2012）305-312
Background: Radiation-induced fibrosis is a serious late complication of radiotherapy. Pentoxifylline-vitamin E has proven effective and safe in clinical trials in the treatment of fibrosis, while the molecular mechanism of its activity is yet unexplored.Methods: Ten patients suffering from radiation-induced enteropathy were treated with pentoxifylline-vitamin E combination with SOMA score as the primary endpoint. In parallel, primary smooth muscle cells isolated from intestinal samples isolated from humans with radiation enteropathy were incubated with pentoxifylline, trolox (vit. E hydrophilic analogous) or their combination. Activation of the TGF-beta 1/Smad and Rho/ROCK pathways was subsequently investigated using Q-RT-PCR, gene reporter, Western-blot, ELISA and immunohistochemistry.Results: Pentoxifylline-vitamin E combination induces regression of symptoms (SOMA) by 41% and 80% at 6 and 18 months. In vitro, pentoxifylline and trolox synergize to inhibit TGF-beta 1 protein and mRNA expression. This inhibitory action is mediated at the transcriptional level and leads to subsequent inhibition of TGF-beta 1/Smad targets (Col I alpha 1, FN1, PAI-1, CTGF), while it has no effect on the Rho/ROCK pathway.Conclusions: The anti-fibrotic effect of combined pentoxifylline-vitamin E is at least in part mediated by inhibition of the TGF-beta 1 cascade. It strengthens previous clinical data showing pentoxifylline-vitamin E synergy and supports its use as a first-line treatment of radiation-induced fibrosis. (C) 2012 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 105 (2012) 305-312