Neurofibromatosis 1 and 2, although involving two different tumour suppressor genes (neurofibromin and merlin, respectively), are both cancer predisposition syndromes that disproportionately affect cells of neural crest origin. New therapeutic approaches for both NF1 and NF2 are badly needed. In promising previous work we demonstrated that two non-steroidal analogues of 2-methoxy-oestradiol (2ME2), STX3451(2-(3-bromo-4,5-dimethoxybenzyl)-7-methoxy-6-sulfamoyloxy-1,2,3,4-tetrahydroisoquinoline), and STX2895 (7-Ethyl-6-sulfamoyloxy-2-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline) reduced tumour cell growth and induced apoptosis in malignant and benign human Neurofibromatosis 1 (NF1) tumour cells. In earlier NF1 mechanism of action studies we found that in addition to their effects on non-classical hormone-sensitive pathways, STX agents acted on the actin- and myosin-cytoskeleton, as well as PI3Kinase and MTOR signaling pathways. Tumour growth in NF2 cells is affected by different inhibitors from those affecting NF1 growth pathways: specifically, NF2 cells are affected by merlin-downstream pathway inhibitors. Because Merlin, the affected tumour suppressor gene in NF2, is also known to be involved in stabilizing membrane-cytoskeletal complexes, as well as in cell proliferation, and apoptosis, we looked for potentially common mechanisms of action in the agents’ effects on NF1 and NF2. We set out to determine whether STX agents could therefore also provide a prospective avenue for treatment of NF2. STX3451 and STX2895 were tested in dose-dependent studies for their effects on growth parameters of malignant and benign NF2 human tumour cell lines in vitro. The mechanisms of action of STX3451 and STX2895 were also analysed. Although neither of the agents tested affected cell growth or apoptosis in the NF2 tumour cell lines tested through the same mechanisms by which they affect these parameters in NF1 tumour cell lines, both agents disrupted actin- and myosin-based cytoskeletal structures in NF2 cell lines, with subsequent effects on growth and cell death. Both STX3451 and STX2895 provide new approaches for inducing cell death and lowering tumour burden in NF2 as well as in NF1, which both have limited treatment options.

中文翻译：

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非甾体氨基磺酸衍生物作为神经纤维瘤病2（NF2）的新治疗方法

神经纤维瘤病1和2尽管涉及两个不同的肿瘤抑制基因（分别为神经纤维蛋白和merlin），但它们都是易患神经rest起源细胞的癌症易感综合症。迫切需要针对NF1和NF2的新治疗方法。在有前途的工作中，我们证明了2-甲氧基-雌二醇（2ME2）的两个非甾体类似物STX3451（2-（3-bromo-4,5-二甲氧基苄基）-7-甲氧基-6-氨磺酰氧基-1,2， 3,4-四氢异喹啉）和STX2895（7-乙基-6-氨磺酰氧基-2-（3,4,5-三甲氧基苄基）-1,2,3,4-四氢异喹啉）减少肿瘤细胞的生长并诱导恶性和良性人类神经纤维瘤病1（NF1）肿瘤细胞。在较早的NF1作用机理研究中，我们发现，除了它们对非经典激素敏感途径的影响外，STX剂作用于肌动蛋白和肌球蛋白的细胞骨架，以及PI3Kinase和MTOR信号通路。NF2细胞中的肿瘤生长受到与影响NF1生长途径的抑制剂不同的抑制剂的影响：具体而言，NF2细胞受到merlin下游途径抑制剂的影响。由于还已知NF2中受影响的肿瘤抑制基因Merlin也参与稳定膜-细胞骨架复合物以及细胞增殖和凋亡，因此我们寻找了可能的常见作用机制，对NF1和NF-κB的作用进行了研究。 NF2。我们着手确定STX药物是否因此也可以为NF2的治疗提供前瞻性途径。在剂量依赖性研究中测试了STX3451和STX2895对体外对恶性和良性NF2人肿瘤细胞系生长参数的影响。还分析了STX3451和STX2895的作用机理。尽管两种试剂均未通过影响NF1肿瘤细胞系中这些参数的相同机制来影响NF2肿瘤细胞系中的细胞生长或凋亡，但两种试剂均破坏了NF2细胞系中基于肌动蛋白和肌球蛋白的细胞骨架结构，对生长和细胞死亡产生后续影响。STX3451和STX2895都提供了新的方法来诱导NF2和NF1中的细胞死亡并降低肿瘤负荷，而这两种方法均具有有限的治疗选择。两种药物都破坏了NF2细胞系中基于肌动蛋白和肌球蛋白的细胞骨架结构，从而对生长和细胞死亡产生了影响。STX3451和STX2895都提供了新的方法来诱导NF2和NF1中的细胞死亡并降低肿瘤负荷，而这两种方法均具有有限的治疗选择。两种药物都破坏了NF2细胞系中基于肌动蛋白和肌球蛋白的细胞骨架结构，从而对生长和细胞死亡产生了影响。STX3451和STX2895都提供了新的方法来诱导NF2和NF1中的细胞死亡并降低肿瘤负荷，而这两种方法均具有有限的治疗选择。