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Nature. 2011 Jul 13;475(7355):231-4. doi: 10.1038/nature10167.

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

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  • 1Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Building 149 13th Street, Charlestown, Massachusetts 02129, USA.

Erratum in

  • Nature. 2012 Jan 26;481(7382):534.

Abstract

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.

©2011 Macmillan Publishers Limited. All rights reserved

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PMID:
21753854
[PubMed - indexed for MEDLINE]
PMCID:
PMC3316487
Free PMC Article

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