Department of Molecular, Cellular and Developmental Biology, 347 UCB, University of Colorado, Boulder, CO 80309-80347, USA.
Dis Model Mech. 2012 May;5(3):342-50. doi: 10.1242/dmm.008722. Epub 2012 Feb 16.
We described previously a screening protocol in Drosophila melanogaster that allows us to identify small molecules that increase the killing effect of ionizing radiation in vivo in a multicellular context. The ability of this screen to identify agents that enhance the effect of radiation in human cancer models has been validated in published proof-of-concept studies. Here we describe an agent, identified by screening through two National Cancer Institute (NCI) small molecule libraries in Drosophila, that increases the effect of radiation. This agent, Bouvardin (NSC 259968), inhibits the elongation step of protein synthesis. We find that Bouvardin enhances the killing effect of X-rays in both Drosophila larvae and in human cancer cells. More detailed analysis showed that Bouvardin also increases the effect of radiation in clonogenic assays and in human cancer xenografts in mice. Finally, we present data that Bouvardin can also increase the efficacy of taxol. Regulation of translation is important to cancer biology. Current therapies target every aspect of cancer cell proliferation from growth factor signaling to cell division, with the exception of translation elongation. Our identification of Bouvardin as an enhancer of radio- and chemo-therapeutic agents suggests that targeting this niche has the potential to improve existing cancer therapies.
我们之前描述了一个在黑腹果蝇中进行的筛选方案，该方案允许我们在多细胞环境中鉴定出能增加体内电离辐射杀伤效应的小分子。该筛选在已发表的概念验证研究中已经验证了其在人类癌症模型中鉴定出增强辐射效果的药物的能力。在这里，我们描述了一种通过在果蝇中筛选两个美国国立癌症研究所（NCI）小分子文库而鉴定出的药物，该药物可增加辐射的效果。该药物，Bouvardin（NSC 259968），抑制蛋白质合成的延伸步骤。我们发现，Bouvardin 增强了 X 射线对果蝇幼虫和人类癌细胞的杀伤效果。更详细的分析表明，Bouvardin 还增加了克隆形成测定和在小鼠中人类癌症异种移植中的辐射效果。最后，我们提供的数据表明，Bouvardin 还可以提高紫杉醇的疗效。翻译的调控对癌症生物学很重要。目前的治疗方法针对从生长因子信号到细胞分裂的各个方面来靶向癌细胞的增殖，除了翻译延伸。我们鉴定出 Bouvardin 作为放射和化疗药物的增强剂，这表明靶向这一领域有可能改善现有的癌症治疗方法。
