Department of Oral and Maxillofacial Plastic Surgery, University Hospital Würzburg, D-97070 Würzburg, Germany.
Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, D-97080 Würzburg, Germany.
Int J Mol Sci. 2019 Mar 15;20(6):1306. doi: 10.3390/ijms20061306.
Inflammation is a central aspect of tumour biology and can contribute significantly to both the origination and progression of tumours. The NFκB pathway is one of the most important signal transduction pathways in inflammation and is, therefore, an excellent target for cancer therapy. In this work, we examined the influence of four NFκB inhibitors-Cortisol, MLN4924, QNZ and TPCA1-on proliferation, inflammation and sensitisation to apoptosis mediated by the death ligand FasL in the HNSCC cell lines PCI1, PCI9, PCI13, PCI52 and SCC25 and in the human dermal keratinocyte cell line HaCaT. We found that the selection of the inhibitor is critical to ensure that cells do not respond by inducing counteracting activities in the context of cancer therapy, e.g., the extreme IL-8 induction mediated by MLN4924 or FasL resistance mediated by Cortisol. However, TPCA1 was qualified by this in vitro study as an excellent therapeutic mediator in HNSCC by four positive qualities: (1) proliferation was inhibited at low μM-range concentrations; (2) TNFα-induced IL-8 secretion was blocked; (3) HNSCC cells were sensitized to TNFα-induced cell death; and (4) FasL-mediated apoptosis was not disrupted.
炎症是肿瘤生物学的一个核心方面，它可以显著促进肿瘤的发生和发展。NFκB 通路是炎症中最重要的信号转导通路之一，因此是癌症治疗的一个极好靶点。在这项工作中，我们研究了四种 NFκB 抑制剂——皮质醇、MLN4924、QNZ 和 TPCA1——对 HNSCC 细胞系 PCI1、PCI9、PCI13、PCI52 和 SCC25 以及人真皮角质形成细胞系 HaCaT 中由死亡配体 FasL 介导的增殖、炎症和凋亡敏感性的影响。我们发现，抑制剂的选择对于确保细胞不会通过在癌症治疗的背景下诱导对抗性活性来做出反应至关重要，例如 MLN4924 介导的极端的 IL-8 诱导或皮质醇介导的 FasL 耐药性。然而，通过这项体外研究，TPCA1 被证明是 HNSCC 的一种极好的治疗介质，具有以下四个积极特性：（1）在低 μM 浓度范围内抑制增殖；（2）阻断 TNFα 诱导的 IL-8 分泌；（3）使 HNSCC 细胞对 TNFα 诱导的细胞死亡敏感；以及（4）不破坏 FasL 介导的凋亡。
