Low-dose paclitaxel modulates tumour fibrosis in gastric cancer.
Low-dose paclitaxel modulates tumour fibrosis in gastric cancer.
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DOI：
10.3892/ijo.2013.1801
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发表时间：
2013-04
影响因子：
5.2
通讯作者：
Ohta T
中科院分区：
文献类型：
--
作者：
Tsukada T;Fushida S;Harada S;Terai S;Yagi Y;Kinoshita J;Oyama K;Tajima H;Ninomiya I;Fujimura T;Ohta T
腹膜播散是胃癌最常见的转移方式，已采用各种治疗方法，但由于存在丰富的纤维成分和获得性耐药性，尚未获得足够好的临床结果。上皮间质转化（EMT）是导致组织纤维化的主要原因之一，转化生长因子-β（TGF-β）在EMT的发生发展中起着关键作用。Smad蛋白在TGF-β信号通路中起重要作用。TGF-β/Smad信号通路可以通过用紫杉醇（PTX）稳定微管来调节。在这里，我们研究了紫杉醇是否可以调节人腹膜甲状旁腺细胞（HPMCs）中的TGF-β/Smad信号传导。为了确定HPMC中的细胞生长抑制剂的浓度，使用PTX、5-氟尿嘧啶和顺铂进行3-（4，5-二甲基噻唑-2-基）-2，5-二苯基溴化四唑（MTT）测定。PTX预处理48 h时，对TGF-β1诱导的人腹膜间质细胞形态学改变产生显著抑制作用的最低浓度为5 nM（细胞活力：87.1± 1.5%，P<0.01）。通过免疫荧光染色、实时定量PCR和蛋白质印迹法评估TGF-β信号级联和各种纤维成分的状态。TGF-β信号诱导的形态学改变、α-SMA表达和I型胶原合成在HPMCs和PTX治疗抑制这些EMT样变化。此外，PTX治疗显着抑制Smad 2磷酸化。这些数据表明，在低剂量下，PTX可以通过抑制人腹膜中的Smad 2磷酸化来显著抑制TGF-β/Smad信号传导途径，并且这可以减少基质纤维化。
Various treatments have been used for peritoneal dissemination, which is the most common mode of metastasis in gastric cancer, but sufficiently good clinical outcomes have not yet been obtained because of the presence of rich fibrous components and acquired drug resistance. Epithelialmesenchymal transition (EMT) is one of the major causes of tissue fibrosis and transforming growth factor-β (TGF-β) has a pivotal function in the progression of EMT. Smad proteins play an important role in the TGF-β signalling pathway. The TGF-β/Smad signalling pathway can be modulated by stabilising microtubules with paclitaxel (PTX). Here, we investigated whether paclitaxel can modulate TGF-β/Smad signalling in human peritoneal methothelial cells (HPMCs). To determine the cytostatic concentrations of antineoplastic agents in HPMCs, a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed using PTX, 5-fluorouracil and cisplatin. The minimum concentration that caused significant inhibition of TGF-β1-induced morphological changes in human peritoneal methothelial cells on pre-treatment with PTX was 5 nM at 48 h (cell viability: 87.1±1.5%, P<0.01). The TGF-β signalling cascade and the status of various fibrous components were evaluated by immunofluorescence staining, real-time quantitative PCR and western blotting. TGF-β signalling induced morphological changes, α-SMA expression and collagen I synthesis in HPMCs and PTX treatment suppressed these EMT-like changes. Moreover, PTX treatment markedly suppressed Smad2 phosphorylation. These data suggest that at a low-dose, PTX can significantly suppress the TGF-β/Smad signalling pathway by inhibiting Smad2 phosphorylation in the human peritoneum and that this can reduce stromal fibrosis.
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影响因子：
45.3
作者：
Markman, M;Bundy, BN;Sickel, J
通讯作者：
Sickel, J
影响因子：
37.8
作者：
Colombo, A;Drzewiecki, J;Russell, ME
通讯作者：
Russell, ME
影响因子：
16
作者：
Dong, CM;Li, ZR;Goldschmidt-Clermont, PJ
通讯作者：
Goldschmidt-Clermont, PJ
影响因子：
5.4
作者：
Lv, Zhi-Dong;Na, Di;Xu, Hui-Mian
通讯作者：
Xu, Hui-Mian
DOI：
10.1073/pnas.90.20.9552
发表时间：
1993-10-15
影响因子：
11.1
作者：
JORDAN, MA;TOSO, RJ;WILSON, L
通讯作者：
WILSON, L