Targeted NF1 cancer therapeutics with multiple modes of action: small molecule hormone-like agents resembling the natural anticancer metabolite, 2-methoxyoestradiol.
Targeted NF1 cancer therapeutics with multiple modes of action: small molecule hormone-like agents resembling the natural anticancer metabolite, 2-methoxyoestradiol.
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具有多种作用模式的靶向 NF1 癌症疗法：类似于天然抗癌代谢物 2-甲氧基雌二醇的小分子激素样药物。
DOI：
10.1038/bjc.2015.345
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发表时间：
2015
影响因子：
8.8
通讯作者：
Barald,KateF
中科院分区：
文献类型：
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作者：
Shen,Yu-chi;Upadhyayula,Ravi;Cevallos,Stephanie;Messick,RyanJ;Hsia,Tammy;Leese,MathewP;Jewett,DouglasM;Ferrer-Torres,Daysha;Roth,ThereseM;Dohle,Wolfgang;Potter,BarryVL;Barald,KateF
背景：NF1患者肿瘤的数量和大小随着青春期和怀孕期间类固醇激素的增加而增加。分娩后肿瘤大小减小，提示激素靶向治疗可能提供一种可行的NF1治疗新方法。我们早期的研究表明，人类NF1肿瘤细胞系在2-甲氧基雌二醇（2ME2）的存在下要么经历凋亡，要么停止生长，2-甲氧基雌二醇是17-β雌二醇的天然抗癌代谢物。先前的磺胺化甾体和2ME2的非甾体衍生物治疗报告显示，除NF1外，激素反应性癌症的肿瘤负荷有希望减少。在这里，我们提出的第一个研究表明，2ME2衍生物也可以提供治疗NF1的途径，目前很少有治疗方案可用。方法：STX3451，（2-（3-溴- 4,5 -二甲氧基苄基）-7-甲氧基-6-磺胺酰氧基- 1,2,3,4 -四氢异喹啉），是2ME2的非甾体磺胺类似物，在恶性和良性NF1人肿瘤细胞系和可变控制神经纤维蛋白表达的细胞系中进行剂量依赖性研究。分析了STX3451的作用机理。结果：我们发现stx3451诱导人恶性周围神经鞘肿瘤（MPNST）细胞系凋亡，即使在雌激素和孕激素升高的情况下。它抑制PI3激酶和mTOR信号通路。它破坏源自人类MPNSTs的细胞系和源自良性丛状神经纤维瘤的细胞中基于肌动蛋白和微管的细胞骨架结构。STX3451选择性地杀死mpnst来源的细胞，但也停止其他肿瘤来源的NF1细胞系的生长。结论：STX3451在治疗方案有限的NF1和其他激素反应性癌症中提供了诱导细胞死亡和降低肿瘤负担的新途径。
Background:Both the number and size of tumours in NF1 patients increase in response to the rise in steroid hormones seen at puberty and during pregnancy. The size of tumours decreases after delivery, suggesting that hormone-targeting therapy might provide a viable new NF1 treatment approach. Our earlier studies demonstrated that human NF1 tumour cell lines either went through apoptosis or ceased growth in the presence of 2-methoxyoestradiol (2ME2), a naturally occurring anticancer metabolite of 17-β estradiol. Previous reports of treatment with sulfamoylated steroidal and non-steroidal derivatives of 2ME2 showed promising reductions in tumour burden in hormone-responsive cancers other than NF1. Here we present the first studies indicating that 2ME2 derivatives could also provide an avenue for treating NF1, for which few treatment options are available.Methods:STX3451,(2-(3-Bromo-4, 5-dimethoxybenzyl)-7-methoxy-6-sulfamoyloxy-1, 2, 3, 4-tetrahydroisoquinoline), a non-steroidal sulphamate analogue of 2ME2, was tested in dose-dependent studies of malignant and benign NF1 human tumour cell lines and cell lines with variable controlled neurofibromin expression. The mechanisms of action of STX3451 were also analysed.Results:We found that STX3451-induced apoptosis in human malignant peripheral nerve sheath tumour (MPNST) cell lines, even in the presence of elevated oestrogen and progesterone. It inhibits both PI3 kinase and mTOR signalling pathways. It disrupts actin-and microtubule-based cytoskeletal structures in cell lines derived from human MPNSTs and in cells derived from benign plexiform neurofibromas. STX3451 selectively kills MPNST-derived cells, but also halts growth of other tumour-derived NF1 cell lines.Conclusion:STX3451 provides a new approach for inducing cell death and lowering tumour burden in NF1 and other hormone-responsive cancers with limited treatment options.