Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Building 149 13th Street, Charlestown, Massachusetts 02129, USA.
Nature. 2011 Jul 13;475(7355):231-4. doi: 10.1038/nature10167.
Malignant transformation, driven by gain-of-function mutations in oncogenes and loss-of-function mutations in tumour suppressor genes, results in cell deregulation that is frequently associated with enhanced cellular stress (for example, oxidative, replicative, metabolic and proteotoxic stress, and DNA damage). Adaptation to this stress phenotype is required for cancer cells to survive, and consequently cancer cells may become dependent upon non-oncogenes that do not ordinarily perform such a vital function in normal cells. Thus, targeting these non-oncogene dependencies in the context of a transformed genotype may result in a synthetic lethal interaction and the selective death of cancer cells. Here we used a cell-based small-molecule screening and quantitative proteomics approach that resulted in the unbiased identification of a small molecule that selectively kills cancer cells but not normal cells. Piperlongumine increases the level of reactive oxygen species (ROS) and apoptotic cell death in both cancer cells and normal cells engineered to have a cancer genotype, irrespective of p53 status, but it has little effect on either rapidly or slowly dividing primary normal cells. Significant antitumour effects are observed in piperlongumine-treated mouse xenograft tumour models, with no apparent toxicity in normal mice. Moreover, piperlongumine potently inhibits the growth of spontaneously formed malignant breast tumours and their associated metastases in mice. Our results demonstrate the ability of a small molecule to induce apoptosis selectively in cells that have a cancer genotype, by targeting a non-oncogene co-dependency acquired through the expression of the cancer genotype in response to transformation-induced oxidative stress.
恶性转化是由癌基因获得功能突变和肿瘤抑制基因失活突变驱动的，导致细胞失控，这通常与增强的细胞应激有关（例如氧化应激、复制应激、代谢应激和蛋白毒性应激以及 DNA 损伤）。为了使癌细胞存活，它们需要适应这种应激表型，因此癌细胞可能会依赖于通常在正常细胞中不起这种重要作用的非癌基因。因此，在转化基因型的背景下靶向这些非癌基因依赖性可能会导致合成致死相互作用并选择性杀死癌细胞。在这里，我们使用基于细胞的小分子筛选和定量蛋白质组学方法，非偏见地鉴定出一种选择性杀死癌细胞而不杀死正常细胞的小分子。胡椒碱可增加具有癌症基因型的癌细胞和正常细胞中的活性氧 (ROS) 水平和细胞凋亡，但对快速或缓慢分裂的原发性正常细胞几乎没有影响。在接受胡椒碱治疗的小鼠异种移植肿瘤模型中观察到显著的抗肿瘤作用，在正常小鼠中没有明显的毒性。此外，胡椒碱能有效抑制自发形成的恶性乳腺肿瘤及其在小鼠中的转移生长。我们的结果表明，小分子通过靶向癌症基因型表达引起的氧化应激反应获得的非癌基因共依赖性，能够选择性地诱导具有癌症基因型的细胞发生细胞凋亡。
