Nintedanib inhibits keloid fibroblast functions by blocking the phosphorylation of multiple kinases and enhancing receptor internalization.
Nintedanib inhibits keloid fibroblast functions by blocking the phosphorylation of multiple kinases and enhancing receptor internalization.
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尼达尼布通过阻断多种激酶的磷酸化并增强受体内化来抑制瘢痕疙瘩成纤维细胞功能
DOI：
10.1038/s41401-020-0381-y
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发表时间：
2020-09
影响因子：
8.2
通讯作者：
Liu W
中科院分区：
文献类型：
--
作者：
Zhou BY;Wang WB;Wu XL;Zhang WJ;Zhou GD;Gao Z;Liu W
瘢痕疙瘩是一种良性皮肤肿瘤，其特征在于其细胞过度增殖活性、侵入正常皮肤、不受控制的生长、细胞外基质的过度产生和沉积以及各种治疗后的高复发率。NATIONAL是一种靶向VEGF、PDGF、FGF和TGF-β受体的受体酪氨酸激酶抑制剂，在抗血管生成和治疗各种类型的癌症方面具有已证实的疗效。在本研究中，我们在体外和离体模型中研究了尼达尼布对瘢痕疙瘩成纤维细胞的影响。瘢痕疙瘩成纤维细胞从收集自49名患者的54个处于活动期的瘢痕疙瘩瘢痕样品中制备。我们发现尼达尼布（1−4 μM）呈剂量依赖性抑制细胞增殖，诱导G 0/G1细胞周期停滞，并抑制瘢痕疙瘩成纤维细胞的迁移和侵袭。该药物还显著抑制胶原蛋白I（COL-1）和III（COL-3）、纤维连接蛋白（FN）和结缔组织生长因子（CTGF）的基因和蛋白表达，以及其他病理因子的基因表达，如α平滑肌肌动蛋白（α-SMA）、纤溶酶原激活物抑制剂-1（派-1）、FK 506结合蛋白10（FKBP 10）、和热休克蛋白47（HSP 47）。此外，尼达尼布治疗显著抑制了p38、JNK、ERK、STAT 3和Smad的磷酸化，增强了各种生长因子受体的内吞作用。使用离体组织外植体模型，我们发现尼达尼布可显著抑制细胞增殖、迁移和胶原蛋白生成。该药物还显着破坏离体微血管结构。总之，我们的结果表明尼达尼布可能成为瘢痕疙瘩全身治疗的潜在靶向药物。
Keloid is a benign skin tumor characterized by its cell hyperproliferative activity, invasion into normal skin, uncontrolled growth, overproduction and deposition of extracellular matrices and high recurrence rate after various therapies. Nintedanib is a receptor tyrosine kinase inhibitor targeting VEGF, PDGF, FGF, and TGF-β receptors with proved efficacy in anti-angiogenesis and in treating various types of cancers. In this study, we investigated the effects of nintedanib on keloid fibroblasts in both in vitro and ex vivo models. Keloid fibroblasts were prepared from 54 keloid scar samples in active stages collected from 49 patients. We found that nintedanib (1−4 μM) dose-dependently suppressed cell proliferation, induced G0/G1 cell cycle arrest, and inhibited migration and invasion of keloid fibroblasts. The drug also significantly inhibited the gene and protein expression of collagen I (COL-1) and III (COL-3), fibronectin (FN), and connective growth factor (CTGF), as well as the gene expression of other pathological factors, such as alpha smooth muscle actin (α-SMA), plasminogen activator inhibitor-1 (PAI-1), FK506-binding protein 10 (FKBP10), and heat shock protein 47 (HSP47) in keloid fibroblasts. Furthermore, nintedanib treatment significantly suppressed the phosphorylation of p38, JNK, ERK, STAT3, and Smad, enhanced endocytosis of various growth factor receptors. Using an ex vivo tissue explant model, we showed that nintedanib significantly suppressed cell proliferation, migration, and collagen production. The drug also significantly disrupted microvessel structure ex vivo. In summary, our results demonstrate that nintedanib is likely to become a potential targeted drug for keloid systemic therapy.
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影响因子：
5.8
作者：
Lehtonen ST;Veijola A;Karvonen H;Lappi-Blanco E;Sormunen R;Korpela S;Zagai U;Sköld MC;Kaarteenaho R
通讯作者：
Kaarteenaho R
影响因子：
5.6
作者：
Ghosh, Asish K.;Vaughan, Douglas E.
通讯作者：
Vaughan, Douglas E.
影响因子：
5.6
作者：
Luo L;Li J;Liu H;Jian X;Zou Q;Zhao Q;Le Q;Chen H;Gao X;He C
通讯作者：
He C
影响因子：
11.5
作者：
Brooks, A. Nigel;Kilgour, Elaine;Smith, Paul D.
通讯作者：
Smith, Paul D.
影响因子：
3.6
作者：
Gao, Zhongyu;Wang, Zimin;Jin, Youxin
通讯作者：
Jin, Youxin