Selective killing of cancer cells by a small molecule targeting the stress response to ROS

摘要

一项化学筛选工作发现，一种名为“荜茇明碱”rn(PL)的小分子是一种能够诱导癌细胞被选择rn性杀死的化合物。“荜茇明碱”通过提高癌细rn胞中的活性氧(ROS)水平来发挥作用。虽然它rn在活体中对几种肿瘤都具有活性，并且与p53rn的状态无关，但它却不影响正常组织、包括迅rn速增殖的非肿瘤细胞。这项工作为通过以rnROS应澈通道为目标来根除癌细胞提出了一rn个新策略，但还需要进一步的研究来识别在rn更大范围的癌症中决定“荜茇明碱”灵敏度的rn因素。%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)1. 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 cells2. 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~(3-5).