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Nature DOI:10.1038/nature10167

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

Publication TypeJournal Article
Year of Publication2011
AuthorsRaj, L, Ide, T, Gurkar, AU, Foley, M, Schenone, M, Li, X, Tolliday, NJ, Golub, TR, Carr, SA, Shamji, AF, Stern, AM, Mandinova, A, Schreiber, SL, Lee, SW
JournalNature
Volume475
Issue7355
Pages231-4
Date Published2011 Jul 13
ISSN1476-4687
KeywordsAnimals, Apoptosis, Breast Neoplasms, Cell Line, Cell Line, Tumor, Cell Transformation, Neoplastic, Comet Assay, Dioxolanes, DNA Damage, Genotype, Mice, Neoplasm Metastasis, Oxidative Stress, Reactive Oxygen Species, Small Molecule Libraries, Xenograft Model Antitumor Assays
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.

DOI10.1038/nature10167
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/21753854?dopt=Abstract

Alternate JournalNature
PubMed ID21753854
PubMed Central IDPMC3316487
Grant ListRC2 CA148399 / CA / NCI NIH HHS / United States
UL1RR024924 / RR / NCRR NIH HHS / United States
P30 DK043351 / DK / NIDDK NIH HHS / United States
RL1HG004671 / HG / NHGRI NIH HHS / United States
R01 CA085681-06 / CA / NCI NIH HHS / United States
R01 CA085681 / CA / NCI NIH HHS / United States
CA080058 / CA / NCI NIH HHS / United States
R01 CA142805-01 / CA / NCI NIH HHS / United States
RL1CA133834 / CA / NCI NIH HHS / United States
RL1GM084437 / GM / NIGMS NIH HHS / United States
R01 CA142805 / CA / NCI NIH HHS / United States
P01 CA080058-02 / CA / NCI NIH HHS / United States
UL1 RR024924 / RR / NCRR NIH HHS / United States
P01 CA080058 / CA / NCI NIH HHS / United States
5 RC2 CA148399-02 / CA / NCI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
CA142805 / CA / NCI NIH HHS / United States
RL1 GM084437 / GM / NIGMS NIH HHS / United States
CA085681 / CA / NCI NIH HHS / United States
CA127247 / CA / NCI NIH HHS / United States
R01 CA127247 / CA / NCI NIH HHS / United States
N01CO12400 / CA / NCI NIH HHS / United States
RL1 HG004671 / HG / NHGRI NIH HHS / United States
RL1 CA133834 / CA / NCI NIH HHS / United States