Bouvardin is a Radiation Modulator with a Novel Mechanism of Action.
Bouvardin is a Radiation Modulator with a Novel Mechanism of Action.
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Bouvardin是具有新型作用机理的辐射调节剂。
DOI：
10.1667/rr14068.1
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发表时间：
2015-10
影响因子：
3.4
通讯作者：
Su TT
中科院分区：
文献类型：
--
作者：
Stickel SA;Gomes NP;Frederick B;Raben D;Su TT
蛋白质合成对于细胞的生长、增殖和存活是必不可少的。翻译因子在许多癌症和临床前模型中过表达，它们的实验抑制已显示出抑制癌症生长。翻译的差异调节也发生在暴露于癌症相关的应激源，如缺氧和电离辐射。已证明，未能调节翻译会干扰遗传毒性应激后的恢复。这些发现表明，翻译的调制，单独或与基因毒素，可能是治疗肿瘤。然而，目前只有两种直接抑制翻译的药物被FDA批准用于肿瘤治疗。我们以前已经确定了蛋白质合成抑制剂，bouvardin在果蝇电离辐射的小分子增强剂的屏幕。Bouvardin是在筛选工程化人类乳腺癌干细胞的选择性抑制剂中独立鉴定的。在这里，我们报告了bouvardin治疗头颈癌（HNC）和神经胶质瘤的临床前模型的效果，这两种癌症类型的放射治疗是最常见的治疗。我们的数据表明，bouvardin治疗阻断翻译延长对人类核糖体，并建议，它这样做是通过阻断从核糖体的延伸因子2的解离。Bouvardin和放射线增强了HNC和胶质瘤细胞的克隆性死亡诱导，虽然通过不同的机制。Bouvardin治疗增强了小鼠HNC肿瘤异种移植物中辐射诱导的抗肿瘤作用。这些数据表明，抑制翻译延伸，特别是与放射治疗相结合，可能是一种有前途的癌症治疗选择。
Protein synthesis is essential for growth, proliferation and survival of cells. Translation factors are overexpressed in many cancers and in preclinical models, their experimental inhibition has been shown to inhibit cancer growth. Differential regulation of translation also occurs upon exposure to cancer-relevant stressors such as hypoxia and ionizing radiation. The failure to regulate translation has been shown to interfere with recovery after genotoxic stress. These findings suggest that modulation of translation, alone or in conjunction with genotoxins, may be therapeutic in oncology. Yet, only two drugs that directly inhibit translation are FDA-approved for oncology therapies used today. We have previously identified the protein synthesis inhibitor, bouvardin in a screen for small molecule enhancers of ionizing radiation in Drosophila melanogaster. Bouvardin was independently identified in a screen for selective inhibitors of engineered human breast cancer stem cells. Here we report the effect of bouvardin treatment in preclinical models of head and neck cancer (HNC) and glioma, two cancer types for which radiation therapy is the most common treatment. Our data show that bouvardin treatment blocked translation elongation on human ribosomes and suggest that it did so by blocking the dissociation of elongation factor 2 from the ribosome. Bouvardin and radiation enhanced the induction of clonogenic death in HNC and glioma cells, although by different mechanisms. Bouvardin treatment enhanced the radiation-induced antitumor effects in HNC tumor xenografts in mice. These data suggest that inhibition of translation elongation, particularly in combination with radiation treatment, may be a promising treatment option for cancer.