Synergistic effect of targeting the epidermal growth factor receptor and hyaluronan synthesis in oesophageal squamous cell carcinoma cells
Synergistic effect of targeting the epidermal growth factor receptor and hyaluronan synthesis in oesophageal squamous cell carcinoma cells
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DOI：
10.1111/bph.13240
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发表时间：
2015-09-01
影响因子：
7.3
通讯作者：
Fischer, J. W.
中科院分区：
文献类型：
--
作者：
Kretschmer, I.;Freudenberger, T.;Fischer, J. W.
背景与目的食管癌是全球第八大常见癌症，其生存率非常低。为了确定食管鳞状细胞癌（ESCC）新的可耐受治疗方案，厄洛替尼在I期和II期研究中进行了中等疗效的测试。由于透明质酸（HA）合成抑制剂4-methylumbelliferone （4-MU）在体外和ESCC异种移植肿瘤中显示出抗癌作用，我们研究了厄洛替尼与4-MU联用是否可以增强其抗癌作用。实验方法厄洛替尼或吉非替尼（1molL(-1)）和4-MU （300molL(-1)）分别作用于escc细胞株，与单药和溶剂对照比较，测定细胞计数、细胞周期进展和迁移情况。关键结果厄洛替尼与4-MU联用可协同抑制ESCC细胞株的增殖。此外，厄洛替尼和4-MU联合使用可显著降低ESCC细胞株KYSE-410在间隙闭合实验中的迁移速度。ERK磷酸化水平的降低可以解释联合治疗组的抗增殖和抗迁移作用。最后，该组合还能够减少多细胞肿瘤球体的生长，这是一种三维细胞培养模型，与ERK1/2磷酸化的持续抑制有关。结论与意义4-MU与厄洛替尼联用对ESCC细胞系具有良好的抗癌作用。
Background and PurposeWorldwide, oesophageal cancer is the eighth most common cancer and has a very poor survival rate. In order to identify new tolerable treatment options for oesophageal squamous cell carcinoma (ESCC), erlotinib was tested with moderate efficacy in phase I and II studies. As 4-methylumbelliferone (4-MU), an hyaluronan (HA) synthesis inhibitor showed anti-cancer effects in vitro, and in ESCC xenograft tumours, we investigated whether the anti-cancer effects of erlotinib could be augmented by combining it with 4-MU.Experimental ApproachESCC cell lines were treated with erlotinib or gefitinib (1molL(-1)) and 4-MU (300molL(-1)), and the cell count, cell cycle progression and migration were determined as compared to the single agents and the solvent-control.Key ResultsThe combination of erlotinib and 4-MU synergistically inhibited the proliferation of ESCC cell lines. Furthermore, the migration speed of ESCC cell line KYSE-410 in gap closure assays was significantly reduced by the combination of erlotinib and 4-MU. Decreased ERK phosphorylation could explain the anti-proliferative and anti-migratory effects in the combined treatment group. Finally, the combination was additionally able to decrease the growth of multicellular tumour spheroids, a three-dimensional cell culture model that was associated with sustained inhibition of ERK1/2 phosphorylation.Conclusions and ImplicationsThe combination of 4-MU and erlotinib showed promising anti-cancer efficacies in the ESCC cell lines.