Letter | Published:

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

Nature volume 475, pages 231234 (14 July 2011) | Download Citation

  • A Corrigendum to this article was published on 25 January 2012
  • A Corrigendum to this article was published on 16 September 2015
  • This article was retracted on 25 July 2018

This article has been updated

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)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 stress3,4,5.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Change history

  • 25 July 2018

    This Article has been retracted; see accompanying Retraction.

References

  1. 1.

    , & Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 136, 823–837 (2009)

  2. 2.

    , , & Poly(ADP-ribose) polymerase (PARP) inhibitors: Exploiting a synthetic lethal strategy in the clinic. CA Cancer J. Clin. 61, 31–49 (2011)

  3. 3.

    & Discovering mechanisms of signaling-mediated cysteine oxidation. Curr. Opin. Chem. Biol. 12, 18–24 (2008)

  4. 4.

    Reactive oxygen species in cancer cells: live by the sword, die by the sword. Cancer Cell 10, 175–176 (2006)

  5. 5.

    , & Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Natl Rev. 8, 579–591 (2009)

  6. 6.

    et al. CDIP, a novel pro-apoptotic gene, regulates TNFα-mediated apoptosis in a p53-dependent manner. EMBO J. 26, 3410–3422 (2007)

  7. 7.

    et al. Piplartine induces inhibition of leukemia cell proliferation triggering both apoptosis and necrosis pathways. Toxicol. In Vitro 21, 1–8 (2007)

  8. 8.

    et al. Creation of human tumour cells with defined genetic elements. Nature 400, 464–468 (1999)

  9. 9.

    et al. PIN1 is an E2F target gene essential for Neu/Ras-induced transformation of mammary epithelial cells. Mol. Cell. Biol. 22, 5281–5295 (2002)

  10. 10.

    , & Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Mol. Cell. Biol. 12, 954–961 (1992)

  11. 11.

    et al. Identifying the proteins to which small-molecule probes and drugs bind in cells. Proc. Natl Acad. Sci. USA 106, 4617–4622 (2009)

  12. 12.

    , , & Human carbonyl reductase 1 is an S-nitrosoglutathione reductase. J. Biol. Chem. 283, 35756–35762 (2008)

  13. 13.

    , , & Direct evidence for the formation of a complex between 1-cysteine peroxiredoxin and glutathione S-transferase π with activity changes in both enzymes. Biochemistry 45, 360–372 (2006)

  14. 14.

    et al. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 458, 780–783 (2009)

  15. 15.

    & Reactive oxygen species: a breath of life or death? Clin. Cancer Res. 13, 789–794 (2007)

  16. 16.

    , , , & Superoxide dismutase as a target for the selective killing of cancer cells. Nature 407, 390–395 (2000)

  17. 17.

    et al. Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by β-phenylethyl isothiocyanate. Cancer Cell 10, 241–252 (2006)

  18. 18.

    , & Mitochondria in cancer cells: what is so special about them? Trends Cell Biol. 18, 165–173 (2008)

  19. 19.

    & Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res. 51, 794–798 (1991)

  20. 20.

    , & Curcumin and cancer cells: how many ways can curry kill tumor cells selectively? Am. Assoc. Pharm. Sci. J. 11, 495–510 (2009)

  21. 21.

    , , & Depletion of intracellular glutathione contributes to JNK-mediated death receptor 5 upregulation and apoptosis induction by the novel synthetic triterpenoid methyl-2-cyano-3, 12-dioxooleana-1, 9-dien-28-oate (CDDO-Me). Cancer Biol. Ther. 5, 492–497 (2006)

  22. 22.

    , , , & The GI-GPx gene is a target for Nrf2. Mol. Cell Biol. 25, 4914–4923 (2005)

  23. 23.

    et al. An exceptionally potent inducer of cytoprotective enzymes: elucidation of the structural features that determine inducer potency and reactivity with KEAP1. J. Biol. Chem. 285, 33747–33755 (2010)

  24. 24.

    et al. Ras proteins induce senescence by altering the intracellular levels of reactive oxygen species. J. Biol. Chem. 274, 7936–7940 (1999)

  25. 25.

    et al. The stress kinase MKK7 couples oncogenic stress to p53 stability and tumor suppression. Nature Genet. 43, 212–219 (2011)

  26. 26.

    , , & Glutathione S-transferase P1–1 (GSTP1–1) inhibits c-Jun N-terminal kinase (JNK1) signaling through interaction with the C terminus. J. Biol. Chem. 276, 20999–21003 (2001)

  27. 27.

    et al. Empirical Bayes analysis of quantitative proteomics experiments. PLoS ONE 4, e7454 (2009)

Download references

Acknowledgements

We thank K. Chu, L. Brown-Endres, E. Lerner and F. Neville for their help in preparing the manuscript, W. C. Hahn for BJ cell lines, V. Band for 76N cells, D. Beer for H1975 cells and K. Todorova, G. Wei, S. Ong, S. Norton and F. An for technical assistance. This project has been supported in part by grants CA142805, CA127247, CA085681 and CA080058 from NIH. This research was supported by the National Cancer Institute’s Initiative for Chemical Genetics Contract (N01-CO-12400) and Cancer Target Discovery and Development Network grant (5 RC2 CA148399-02), as well as the National Institutes of Health Genomics Based Drug Discovery—Target ID Project Grant (RL1HG004671, which is administratively linked to National Institutes of Health Grants RL1CA133834, RL1GM084437 and UL1RR024924). S.L.S. is an Investigator with the Howard Hughes Medical Institute.

Author information

Affiliations

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

    • Lakshmi Raj
    • , Takao Ide
    • , Aditi U. Gurkar
    • , Anna Mandinova
    •  & Sam W. Lee
  2. Broad Institute of Harvard and MIT, 7 Cambridge Center, Massachusetts 02142, USA

    • Michael Foley
    • , Monica Schenone
    • , Xiaoyu Li
    • , Nicola J. Tolliday
    • , Todd R. Golub
    • , Steven A. Carr
    • , Alykhan F. Shamji
    • , Andrew M. Stern
    • , Anna Mandinova
    • , Stuart L. Schreiber
    •  & Sam W. Lee

Authors

  1. Search for Lakshmi Raj in:

  2. Search for Takao Ide in:

  3. Search for Aditi U. Gurkar in:

  4. Search for Michael Foley in:

  5. Search for Monica Schenone in:

  6. Search for Xiaoyu Li in:

  7. Search for Nicola J. Tolliday in:

  8. Search for Todd R. Golub in:

  9. Search for Steven A. Carr in:

  10. Search for Alykhan F. Shamji in:

  11. Search for Andrew M. Stern in:

  12. Search for Anna Mandinova in:

  13. Search for Stuart L. Schreiber in:

  14. Search for Sam W. Lee in:

Contributions

L.R. and T.I. conducted most of the experimental work. A.U.G., M.S. and X.L. made critical experimental contributions. N.J.T., A.M.S., T.R.G., S.A.C., A.F.S. and M.F. designed the experimental plans, analysed and interpreted the data. A.M., S.L.S. and S.W.L. designed and directed the project and drafted the manuscript.

Competing interests

S.W.L., A.M. and M.F. are co-founders and consultants of Canthera Therapeutics Inc., which pursues cancer therapeutics that act through ROS mechanisms.

Corresponding authors

Correspondence to Anna Mandinova or Stuart L. Schreiber or Sam W. Lee.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    The file contains Supplementary Methods, Supplementary Tables 1-2, Supplementary Figures 1-33 with legends and additional references.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nature10167

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.