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  • Review Article
  • Published:

Modulation of oxidative stress as an anticancer strategy

Nature Reviews Drug Discovery volume 12, pages 931–947 (2013)Cite this article

Subjects

Key Points

  • The role of reactive oxygen species (ROS) in tumorigenesis is controversial, as they have been shown to have both tumour-promoting and tumour-inhibiting properties.

  • Although low to moderate ROS levels can be beneficial to cells by promoting proliferation pathways and DNA mutagenesis, high ROS levels can instead become detrimental and induce cell death.

  • Recent work has shown that multiple antioxidant pathways that inhibit ROS are upregulated during tumour initiation and progression.

  • These antioxidant pathways are composed of a multitude of both metabolic and non-metabolic enzymes, many of which can be targeted for inhibition.

  • Numerous standard chemotherapies are cytotoxic towards cancer cells owing to their ability to induce drastic increases in ROS levels.

  • The development of novel targeted therapies against antioxidant pathways may yield considerable benefits to the field of cancer treatment.

Abstract

The regulation of oxidative stress is an important factor in both tumour development and responses to anticancer therapies. Many signalling pathways that are linked to tumorigenesis can also regulate the metabolism of reactive oxygen species (ROS) through direct or indirect mechanisms. High ROS levels are generally detrimental to cells, and the redox status of cancer cells usually differs from that of normal cells. Because of metabolic and signalling aberrations, cancer cells exhibit elevated ROS levels. The observation that this is balanced by an increased antioxidant capacity suggests that high ROS levels may constitute a barrier to tumorigenesis. However, ROS can also promote tumour formation by inducing DNA mutations and pro-oncogenic signalling pathways. These contradictory effects have important implications for potential anticancer strategies that aim to modulate levels of ROS. In this Review, we address the controversial role of ROS in tumour development and in responses to anticancer therapies, and elaborate on the idea that targeting the antioxidant capacity of tumour cells can have a positive therapeutic impact.

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Figure 1: Determination of cellular redox status by a balance between levels of ROS inducers and ROS scavengers.
Figure 2: NRF2 as the master regulator of antioxidant responses.
Figure 3: NRF2, p53 and FOXOs support complementary antioxidant pathways.
Figure 4: Multiple tumour supporter pathways promote GSH synthesis and regeneration.
Figure 5: The antioxidant pathways that drive ROS detoxification.
Figure 6: Interplay between ROS regulation and tumorigenesis at different stages.

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References

  1. Cairns, R. A., Harris, I. S. & Mak, T. W. Regulation of cancer cell metabolism. Nature Rev. Cancer 11, 85–95 (2011).

    Article  CAS  Google Scholar 

  2. Diehn, M. et al. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 458, 780–783 (2009). This paper demonstrates that the mechanism by which cancer stem cells survive radiation (while the remaining tumour is eradicated) is through increased antioxidants and lower ROS levels.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Weinstein, I. B. & Joe, A. Oncogene addiction. Cancer Res. 68, 3077–3080 (2008).

    Article  CAS  PubMed  Google Scholar 

  4. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  PubMed  Google Scholar 

  5. Jones, R. G. & Thompson, C. B. Tumor suppressors and cell metabolism: a recipe for cancer growth. Genes Dev. 23, 537–548 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Finkel, T. Signal transduction by mitochondrial oxidants. J. Biol. Chem. 287, 4434–4440 (2012).

    Article  CAS  PubMed  Google Scholar 

  7. Handy, D. E. & Loscalzo, J. Redox regulation of mitochondrial function. Antioxid. Redox Signal. 16, 1323–1367 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Schrader, M. & Fahimi, H. D. Peroxisomes and oxidative stress. Biochim. Biophys. Acta 1763, 1755–1766 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Malhotra, J. D. & Kaufman, R. J. Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword? Antioxid. Redox Signal. 9, 2277–2293 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Sena, L. A. & Chandel, N. S. Physiological roles of mitochondrial reactive oxygen species. Mol. Cell 48, 158–167 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Janssen-Heininger, Y. M. et al. Redox-based regulation of signal transduction: principles, pitfalls, and promises. Free Radic. Biol. Med. 45, 1–17 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Rhee, S. G. H2O2, a necessary evil for cell signaling. Science 312, 1882–1883 (2006).

    Article  PubMed  Google Scholar 

  13. Naik, E. & Dixit, V. M. Mitochondrial reactive oxygen species drive proinflammatory cytokine production. J. Exp. Med. 208, 417–420 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Gloire, G., Legrand-Poels, S. & Piette, J. NF-κB activation by reactive oxygen species: fifteen years later. Biochem. Pharmacol. 72, 1493–1505 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. Oberley, L. W. Free radicals and diabetes. Free Radic. Biol. Med. 5, 113–124 (1988).

    Article  CAS  PubMed  Google Scholar 

  16. Trachootham, D., Alexandre, J. & Huang, P. Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nature Rev. Drug Discov. 8, 579–591 (2009).

    Article  CAS  Google Scholar 

  17. Ranjan, P. et al. Redox-dependent expression of cyclin D1 and cell proliferation by Nox1 in mouse lung epithelial cells. Antioxid. Redox Signal. 8, 1447–1459 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Martindale, J. L. & Holbrook, N. J. Cellular response to oxidative stress: signaling for suicide and survival. J. Cell. Physiol. 192, 1–15 (2002).

    Article  CAS  PubMed  Google Scholar 

  19. Leslie, N. R. et al. Redox regulation of PI 3-kinase signalling via inactivation of PTEN. EMBO J. 22, 5501–5510 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Xu, D., Rovira, I. I. & Finkel, T. Oxidants painting the cysteine chapel: redox regulation of PTPs. Dev. Cell 2, 251–252 (2002).

    Article  CAS  PubMed  Google Scholar 

  21. Harris, I. S. et al. PTPN12 promotes resistance to oxidative stress and supports tumorigenesis by regulating FOXO signaling. Oncogene http://dx.doi.org/10.1038/onc.2013.24 (2013).

  22. Shi, X., Zhang, Y., Zheng, J. & Pan, J. Reactive oxygen species in cancer stem cells. Antioxid. Redox Signal. 16, 1215–1228 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kim, H. M. et al. Increased CD13 expression reduces reactive oxygen species, promoting survival of liver cancer stem cells via an epithelial-mesenchymal transition-like phenomenon. Ann. Surg. Oncol. 19 (Suppl. 3), 539–548 (2012).

    Article  Google Scholar 

  24. Schafer, Z. T. et al. Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment. Nature 461, 109–113 (2009). This study reported that, upon matrix detachment, cancer cells undergo an increase in ROS levels, which can be alleviated by oncogene expression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sporn, M. B. & Liby, K. T. NRF2 and cancer: the good, the bad and the importance of context. Nature Rev. Cancer 12, 564–571 (2012).

    Article  CAS  Google Scholar 

  26. Taguchi, K., Motohashi, H. & Yamamoto, M. Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution. Genes Cells 16, 123–140 (2011).

    Article  CAS  PubMed  Google Scholar 

  27. Meister, A. Selective modification of glutathione metabolism. Science 220, 472–477 (1983).

    Article  CAS  PubMed  Google Scholar 

  28. Sasaki, H. et al. Electrophile response element-mediated induction of the cystine/glutamate exchange transporter gene expression. J. Biol. Chem. 277, 44765–44771 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Mandal, P. K. et al. System x(c)- and thioredoxin reductase 1 cooperatively rescue glutathione deficiency. J. Biol. Chem. 285, 22244–22253 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Johansson, L., Gafvelin, G. & Arner, E. S. Selenocysteine in proteins — properties and biotechnological use. Biochim. Biophys. Acta 1726, 1–13 (2005).

    Article  CAS  PubMed  Google Scholar 

  31. Zhang, W. et al. Stromal control of cystine metabolism promotes cancer cell survival in chronic lymphocytic leukaemia. Nature Cell Biol. 14, 276–286 (2012). This paper identifies the functional role of CD44 in increasing cystine uptake and lowering ROS levels.

    Article  CAS  PubMed  Google Scholar 

  32. Ishimoto, T. et al. CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc− and thereby promotes tumor growth. Cancer Cell 19, 387–400 (2011).

    Article  CAS  PubMed  Google Scholar 

  33. McGrath-Morrow, S. et al. Nrf2 increases survival and attenuates alveolar growth inhibition in neonatal mice exposed to hyperoxia. Am. J. Physiol. Lung Cell. Mol. Physiol. 296, L565–L573 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Thimmulappa, R. K. et al. Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. Cancer Res. 62, 5196–5203 (2002).

    CAS  PubMed  Google Scholar 

  35. Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Mardis, E. R. et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N. Engl. J. Med. 361, 1058–1066 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Gross, S. et al. Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J. Exp. Med. 207, 339–344 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Figueroa, M. E. et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18, 553–567 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Mitsuishi, Y. et al. Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell 22, 66–79 (2012).

    Article  CAS  PubMed  Google Scholar 

  41. Arner, E. S. & Holmgren, A. Physiological functions of thioredoxin and thioredoxin reductase. Eur. J. Biochem. 267, 6102–6109 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Chorley, B. N. et al. Identification of novel NRF2-regulated genes by ChIP-Seq: influence on retinoid X receptor alpha. Nucleic Acids Res. 40, 7416–7429 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kim, Y. J. et al. Human prx1 gene is a target of Nrf2 and is up-regulated by hypoxia/reoxygenation: implication to tumor biology. Cancer Res. 67, 546–554 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. Gutteridge, J. M. Iron promoters of the Fenton reaction and lipid peroxidation can be released from haemoglobin by peroxides. FEBS Lett. 201, 291–295 (1986).

    Article  CAS  PubMed  Google Scholar 

  45. Gozzelino, R., Jeney, V. & Soares, M. P. Mechanisms of cell protection by heme oxygenase-1. Annu. Rev. Pharmacol. Toxicol. 50, 323–354 (2010).

    Article  CAS  PubMed  Google Scholar 

  46. Alam, J. et al. Nrf2, a Cap'n'Collar transcription factor, regulates induction of the heme oxygenase-1 gene. J. Biol. Chem. 274, 26071–26078 (1999).

    Article  CAS  PubMed  Google Scholar 

  47. Orino, K. et al. Ferritin and the response to oxidative stress. Biochem. J. 357, 241–247 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Weinberg, E. D. The role of iron in cancer. Eur. J. Cancer Prev. 5, 19–36 (1996).

    CAS  PubMed  Google Scholar 

  49. Kops, G. J. et al. Direct control of the Forkhead transcription factor AFX by protein kinase B. Nature 398, 630–634 (1999).

    Article  CAS  PubMed  Google Scholar 

  50. Brunet, A. et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96, 857–868 (1999).

    Article  CAS  PubMed  Google Scholar 

  51. Brunet, A. et al. Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a). Mol. Cell. Biol. 21, 952–965 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Greer, E. L. & Brunet, A. FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene 24, 7410–7425 (2005).

    Article  CAS  PubMed  Google Scholar 

  53. Essers, M. A. et al. FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK. EMBO J. 23, 4802–4812 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Lehtinen, M. K. et al. A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span. Cell 125, 987–1001 (2006).

    Article  CAS  PubMed  Google Scholar 

  55. Nemoto, S. & Finkel, T. Redox regulation of forkhead proteins through a p66shc-dependent signaling pathway. Science 295, 2450–2452 (2002).

    Article  CAS  PubMed  Google Scholar 

  56. Yalcin, S. et al. Foxo3 is essential for the regulation of ataxia telangiectasia mutated and oxidative stress-mediated homeostasis of hematopoietic stem cells. J. Biol. Chem. 283, 25692–25705 (2008).

    Article  CAS  PubMed  Google Scholar 

  57. Greer, E. L. et al. The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor. J. Biol. Chem. 282, 30107–30119 (2007).

    Article  CAS  PubMed  Google Scholar 

  58. Cheng, Z. et al. Foxo1 integrates insulin signaling with mitochondrial function in the liver. Nature Med. 15, 1307–1311 (2009).

    Article  CAS  PubMed  Google Scholar 

  59. Mei, Y. et al. FOXO3a-dependent regulation of Pink1 (Park6) mediates survival signaling in response to cytokine deprivation. Proc. Natl Acad. Sci. USA 106, 5153–5158 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Martin, S. A., Hewish, M., Sims, D., Lord, C. J. & Ashworth, A. Parallel high throughput RNA interference screens identify PINK1 as a potential therapeutic target for the treatment of DNA mismatch repair deficient cancers. Cancer Res. 71, 1836–1848 (2011).

    Article  CAS  PubMed  Google Scholar 

  61. Nogueira, V. et al. Akt determines replicative senescence and oxidative or oncogenic premature senescence and sensitizes cells to oxidative apoptosis. Cancer Cell 14, 458–470 (2008). This paper reports the discovery that hyperactivation of the PI3K–AKT pathway can sensitize cancer cells to oxidative stress owing to the inactivation of FOXO factors and the resulting decrease in the expression of antioxidant enzymes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Kops, G. J. et al. Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature 419, 316–321 (2002).

    Article  CAS  PubMed  Google Scholar 

  63. Woo, H. A., Bae, S. H., Park, S. & Rhee, S. G. Sestrin 2 is not a reductase for cysteine sulfinic acid of peroxiredoxins. Antioxid. Redox Signal. 11, 739–745 (2009).

    Article  CAS  PubMed  Google Scholar 

  64. Vousden, K. H. & Ryan, K. M. p53 and metabolism. Nature Rev. Cancer 9, 691–700 (2009).

    Article  CAS  Google Scholar 

  65. Bensaad, K. et al. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126, 107–120 (2006). This paper identifies the role of the novel p53 gene TIGAR , which supports NADPH production by diverting metabolites into the PPP.

    Article  CAS  PubMed  Google Scholar 

  66. Suzuki, S. et al. Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species. Proc. Natl Acad. Sci. USA 107, 7461–7466 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Gao, P. et al. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458, 762–765 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Chen, W. et al. Direct interaction between Nrf2 and p21(Cip1/WAF1) upregulates the Nrf2-mediated antioxidant response. Mol. Cell 34, 663–673 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Seoane, J., Le, H. V., Shen, L., Anderson, S. A. & Massague, J. Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation. Cell 117, 211–223 (2004).

    Article  CAS  PubMed  Google Scholar 

  70. Meiller, A. et al. p53-dependent stimulation of redox-related genes in the lymphoid organs of γ-irradiated mice — identification of haeme-oxygenase 1 as a direct p53 target gene. Nucleic Acids Res. 35, 6924–6934 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Pinnix, Z. K. et al. Ferroportin and iron regulation in breast cancer progression and prognosis. Sci. Transl. Med. 2, 43ra56 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Hayes, J. D., McMahon, M., Chowdhry, S. & Dinkova-Kostova, A. T. Cancer chemoprevention mechanisms mediated through the Keap1–Nrf2 pathway. Antioxid. Redox Signal. 13, 1713–1748 (2010).

    Article  CAS  PubMed  Google Scholar 

  73. Hu, R., Saw, C. L., Yu, R. & Kong, A. N. Regulation of NF-E2-related factor 2 signaling for cancer chemoprevention: antioxidant coupled with antiinflammatory. Antioxid. Redox Signal. 13, 1679–1698 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Frezza, C. et al. Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase. Nature 477, 225–228 (2011).

    Article  CAS  PubMed  Google Scholar 

  75. DeNicola, G. M. et al. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 475, 106–109 (2011). This study shows that the physiological expression of oncogenes can lead to decreased ROS levels through NRF2 antioxidant transcription.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Clements, C. M., McNally, R. S., Conti, B. J., Mak, T. W. & Ting, J. P. DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. Proc. Natl Acad. Sci. USA 103, 15091–15096 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Kim, R. H. et al. DJ-1, a novel regulator of the tumor suppressor PTEN. Cancer Cell 7, 263–273 (2005).

    Article  CAS  PubMed  Google Scholar 

  78. Vasseur, S. et al. DJ-1/PARK7 is an important mediator of hypoxia-induced cellular responses. Proc. Natl Acad. Sci. USA 106, 1111–1116 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Vasseur, S. et al. Consequences of DJ-1 upregulation following p53 loss and cell transformation. Oncogene 31, 664–670 (2012).

    Article  CAS  PubMed  Google Scholar 

  80. Lee, J. & Wolfgang, M. J. Metabolomic profiling reveals a role for CPT1c in neuronal oxidative metabolism. BMC Biochem. 13, 23 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Zaugg, K. et al. Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress. Genes Dev. 25, 1041–1051 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Sanchez-Macedo, N. et al. Depletion of the novel p53-target gene carnitine palmitoyltransferase 1C delays tumor growth in the neurofibromatosis type I tumor model. Cell Death Differ. 20, 659–668 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Kim, Y. R. et al. Oncogenic NRF2 mutations in squamous cell carcinomas of oesophagus and skin. J. Pathol. 220, 446–451 (2010).

    Article  CAS  PubMed  Google Scholar 

  84. Shibata, T. et al. Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy. Proc. Natl Acad. Sci. USA 105, 13568–13573 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Hayes, J. D. & McMahon, M. NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer. Trends Biochem. Sci. 34, 176–188 (2009).

    Article  CAS  PubMed  Google Scholar 

  86. Tenbaum, S. P. et al. β-catenin confers resistance to PI3K and AKT inhibitors and subverts FOXO3a to promote metastasis in colon cancer. Nature Med. 18, 892–901 (2012).

    Article  CAS  PubMed  Google Scholar 

  87. Naka, K. et al. TGF-β–FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature 463, 676–680 (2010).

    Article  CAS  PubMed  Google Scholar 

  88. Sykes, S. M. et al. AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias. Cell 146, 697–708 (2011).

    Article  CAS  PubMed  Google Scholar 

  89. Burgering, B. M. & Medema, R. H. Decisions on life and death: FOXO forkhead transcription factors are in command when PKB/Akt is off duty. J. Leukoc. Biol. 73, 689–701 (2003).

    Article  CAS  PubMed  Google Scholar 

  90. Olanich, M. E. & Barr, F. G. A call to ARMS: targeting the PAX3-FOXO1 gene in alveolar rhabdomyosarcoma. Expert Opin. Ther. Targets 17, 607–623 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. del Peso, L., Gonzalez, V. M., Hernandez, R., Barr, F. G. & Nunez, G. Regulation of the forkhead transcription factor FKHR, but not the PAX3-FKHR fusion protein, by the serine/threonine kinase Akt. Oncogene 18, 7328–7333 (1999).

    Article  CAS  PubMed  Google Scholar 

  92. Li, B., Gordon, G. M., Du, C. H., Xu, J. & Du, W. Specific killing of Rb mutant cancer cells by inactivating TSC2. Cancer Cell 17, 469–480 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Jeon, S. M., Chandel, N. S. & Hay, N. AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature 485, 661–665 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Bae, I. et al. BRCA1 induces antioxidant gene expression and resistance to oxidative stress. Cancer Res. 64, 7893–7909 (2004).

    Article  CAS  PubMed  Google Scholar 

  95. Saha, T., Rih, J. K. & Rosen, E. M. BRCA1 down-regulates cellular levels of reactive oxygen species. FEBS Lett. 583, 1535–1543 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Gorrini, C. et al. BRCA1 interacts with Nrf2 to regulate antioxidant signaling and cell survival. J. Exp. Med. 210, 1529–1544 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Barzilai, A., Rotman, G. & Shiloh, Y. ATM deficiency and oxidative stress: a new dimension of defective response to DNA damage. DNA Repair 1, 3–25 (2002).

    Article  CAS  PubMed  Google Scholar 

  98. Ito, K. et al. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature 431, 997–1002 (2004).

    Article  CAS  PubMed  Google Scholar 

  99. Guo, Z., Kozlov, S., Lavin, M. F., Person, M. D. & Paull, T. T. ATM activation by oxidative stress. Science. 330, 517–521 (2010).

    Article  CAS  PubMed  Google Scholar 

  100. Alexander, A. et al. ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS. Proc. Natl Acad. Sci. USA 107, 4153–4158 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Adam, J. et al. Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling. Cancer Cell 20, 524–537 (2011). This paper demonstrates that NRF2 is stabilized upon loss of the tumour suppressor gene fumarate hydratase.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Ooi, A. et al. An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma. Cancer Cell 20, 511–523 (2011).

    Article  CAS  PubMed  Google Scholar 

  103. Sullivan, L. B. et al. The proto-oncometabolite fumarate binds glutathione to amplify ROS-dependent signaling. Mol. Cell 51, 236–248 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Mazurek, S., Boschek, C. B., Hugo, F. & Eigenbrodt, E. Pyruvate kinase type M2 and its role in tumor growth and spreading. Semin. Cancer Biol. 15, 300–308 (2005).

    Article  CAS  PubMed  Google Scholar 

  105. Christofk, H. R. et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452, 230–233 (2008).

    Article  CAS  PubMed  Google Scholar 

  106. Christofk, H. R., Vander Heiden, M. G., Wu, N., Asara, J. M. & Cantley, L. C. Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature 452, 181–186 (2008).

    Article  CAS  PubMed  Google Scholar 

  107. Vander Heiden, M. G. et al. Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Science 329, 1492–1499 (2010).

    Article  CAS  PubMed  Google Scholar 

  108. Anastasiou, D. et al. Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to antioxidant responses. Science 334, 1278–1283 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Locasale, J. W. et al. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nature Genet. 43, 869–874 (2011).

    Article  CAS  PubMed  Google Scholar 

  110. Possemato, R. et al. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature 476, 346–350 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Jain, M. et al. Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science 336, 1040–1044 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Chaneton, B. et al. Serine is a natural ligand and allosteric activator of pyruvate kinase M2. Nature 491, 458–462 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Goodison, S., Urquidi, V. & Tarin, D. CD44 cell adhesion molecules. Mol. Pathol. 52, 189–196 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Zoller, M. CD44: can a cancer-initiating cell profit from an abundantly expressed molecule? Nature Rev. Cancer 11, 254–267 (2011).

    Article  CAS  Google Scholar 

  115. Blot, W. J. et al. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J. Natl Cancer Inst. 85, 1483–1492 (1993).

    Article  CAS  PubMed  Google Scholar 

  116. Qiao, Y. L. et al. Total and cancer mortality after supplementation with vitamins and minerals: follow-up of the Linxian General Population Nutrition Intervention Trial. J. Natl Cancer Inst. 101, 507–518 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Zhang, W. et al. Vitamin intake and liver cancer risk: a report from two cohort studies in China. J. Natl Cancer Inst. 104, 1173–1181 (2012).

    Article  CAS  PubMed  Google Scholar 

  118. Hurst, R. et al. Selenium and prostate cancer: systematic review and meta-analysis. Am. J. Clin. Nutr. 96, 111–122 (2012).

    Article  CAS  PubMed  Google Scholar 

  119. Richman, E. L. & Chan, J. M. Selenium and prostate cancer: the puzzle isn't finished yet. Am. J. Clin. Nutr. 96, 1–2 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Klein, E. A. et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 306, 1549–1556 (2011). This was the first large study on the link between vitamin E supplementation and cancer risk, in contrast to early observations suggesting that vitamin E has a protective effect against cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Su, Z. Y. et al. A perspective on dietary phytochemicals and cancer chemoprevention: oxidative stress, Nrf2, and epigenomics. Top. Curr. Chem. 329, 133–162 (2012).

    Article  CAS  Google Scholar 

  122. Kim, Y. S., Farrar, W., Colburn, N. H. & Milner, J. A. Cancer stem cells: potential target for bioactive food components. J. Nutrit. Biochem. 23, 691–698 (2012).

    Article  CAS  Google Scholar 

  123. Conklin, K. A. Chemotherapy-associated oxidative stress: impact on chemotherapeutic effectiveness. Integr. Cancer Ther. 3, 294–300 (2004).

    Article  CAS  PubMed  Google Scholar 

  124. Barrera, G. Oxidative stress and lipid peroxidation products in cancer progression and therapy. ISRN Oncol. 2012, 137289 (2012).

    PubMed  PubMed Central  Google Scholar 

  125. Santiago-Arteche, R. et al. Cancer chemotherapy reduces plasma total polyphenols and total antioxidants capacity in colorectal cancer patients. Mol. Biol. Rep. 39, 9355–9360 (2012).

    Article  CAS  PubMed  Google Scholar 

  126. Kaufmann, S. H. & Earnshaw, W. C. Induction of apoptosis by cancer chemotherapy. Exp. Cell Res. 256, 42–49 (2000).

    Article  CAS  PubMed  Google Scholar 

  127. Miller, W. H. et al. Mechanisms of action of arsenic trioxide. Cancer Res. 62, 3893–3903 (2002).

    CAS  PubMed  Google Scholar 

  128. Yi, J. et al. The inherent cellular level of reactive oxygen species: one of the mechanisms determining apoptotic susceptibility of leukemic cells to arsenic trioxide. Apoptosis 7, 209–215 (2002).

    Article  CAS  PubMed  Google Scholar 

  129. Longley, D. B., Harkin, D. P. & Johnston, P. G. 5-fluorouracil: mechanisms of action and clinical strategies. Nature Rev. Cancer 3, 330–338 (2003).

    Article  CAS  Google Scholar 

  130. Hwang, P. M. et al. Ferredoxin reductase affects p53-dependent, 5-fluorouracil-induced apoptosis in colorectal cancer cells. Nature Med. 7, 1111–1117 (2001).

    Article  CAS  PubMed  Google Scholar 

  131. Hwang, I. T. et al. Drug resistance to 5-FU linked to reactive oxygen species modulator 1. Biochem. Biophys. Res. Commun. 359, 304–310 (2007).

    Article  CAS  PubMed  Google Scholar 

  132. Zhang, Q. et al. Involvement of reactive oxygen species in 2-methoxyestradiol-induced apoptosis in human neuroblastoma cells. Cancer Lett. 313, 201–210 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Kachadourian, R. et al. 2-methoxyestradiol does not inhibit superoxide dismutase. Arch. Biochem. Biophys. 392, 349–353 (2001).

    Article  CAS  PubMed  Google Scholar 

  134. Lai, W. L. & Wong, N. S. ROS mediates 4HPR-induced posttranscriptional expression of the Gadd153 gene. Free Radic. Biol. Med. 38, 1585–1593 (2005).

    Article  CAS  PubMed  Google Scholar 

  135. Apraiz, A. et al. Dihydroceramide accumulation and reactive oxygen species are distinct and nonessential events in 4-HPR-mediated leukemia cell death. Biochem. Cell Biol. 90, 209–223 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Neckers, L. & Workman, P. Hsp90 molecular chaperone inhibitors: are we there yet? Clin. Cancer Res. 18, 64–76 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Hao, H. et al. HSP90 and its inhibitors. Oncol. Rep. 23, 1483–1492 (2010).

    CAS  PubMed  Google Scholar 

  138. Scarbrough, P. M. et al. Simultaneous inhibition of glutathione- and thioredoxin-dependent metabolism is necessary to potentiate 17AAG-induced cancer cell killing via oxidative stress. Free Radic. Biol. Med. 52, 436–443 (2012).

    Article  CAS  PubMed  Google Scholar 

  139. De Raedt, T. et al. Exploiting cancer cell vulnerabilities to develop a combination therapy for Ras-driven tumors. Cancer Cell 20, 400–413 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Metzger-Filho, O. et al. Dissecting the heterogeneity of triple-negative breast cancer. J. Clin. Oncol. 30, 1879–1887 (2012).

    Article  CAS  PubMed  Google Scholar 

  141. Masaoka, A., Horton, J. K., Beard, W. A. & Wilson, S. H. DNA polymerase beta and PARP activities in base excision repair in living cells. DNA Repair 8, 1290–1299 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Luo, X. & Kraus, W. L. On PAR with PARP: cellular stress signaling through poly(ADP-ribose) and PARP-1. Genes Dev. 26, 417–432 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Berndtsson, M. et al. Acute apoptosis by cisplatin requires induction of reactive oxygen species but is not associated with damage to nuclear DNA. Int. J. Cancer 120, 175–180 (2007).

    Article  CAS  PubMed  Google Scholar 

  144. Kummar, S. et al. Advances in using PARP inhibitors to treat cancer. BMC Med. 10, 25 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Rottenberg, S. et al. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc. Natl Acad. Sci. USA 105, 17079–17084 (2008). The discovery of PARP inhibitors have brought hope in the treatment of BRCA1-mutated cancers. This work shows the efficacy of PARP inhibitors in combination with platinum drugs.

    Article  PubMed  PubMed Central  Google Scholar 

  146. Evers, B. et al. Selective inhibition of BRCA2-deficient mammary tumor cell growth by AZD2281 and cisplatin. Clin. Cancer Res. 14, 3916–3925 (2008).

    Article  CAS  PubMed  Google Scholar 

  147. Michels, J. et al. Cisplatin resistance associated with PARP hyperactivation. Cancer Res. 73, 2271–2280 (2013).

    Article  CAS  PubMed  Google Scholar 

  148. Michels, J. et al. Synergistic interaction between cisplatin and PARP inhibitors in non-small cell lung cancer. Cell Cycle 12, 877–883 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Yoshida, T., Goto, S., Kawakatsu, M., Urata, Y. & Li, T. S. Mitochondrial dysfunction, a probable cause of persistent oxidative stress after exposure to ionizing radiation. Free Radic. Res. 46, 147–153 (2012).

    Article  CAS  PubMed  Google Scholar 

  150. Wang, Y. et al. Total body irradiation causes residual bone marrow injury by induction of persistent oxidative stress in murine hematopoietic stem cells. Free Radic. Biol. Med. 48, 348–356 (2010).

    Article  CAS  PubMed  Google Scholar 

  151. Voorhees, P. M., Dees, E. C., O'Neil, B. & Orlowski, R. Z. The proteasome as a target for cancer therapy. Clin. Cancer Res. 9, 6316–6325 (2003).

    CAS  PubMed  Google Scholar 

  152. Joazeiro, C. A., Anderson, K. C. & Hunter, T. Proteasome inhibitor drugs on the rise. Cancer Res. 66, 7840–7842 (2006).

    Article  CAS  PubMed  Google Scholar 

  153. Papa, L., Gomes, E. & Rockwell, P. Reactive oxygen species induced by proteasome inhibition in neuronal cells mediate mitochondrial dysfunction and a caspase-independent cell death. Apoptosis 12, 1389–1405 (2007).

    Article  CAS  PubMed  Google Scholar 

  154. Chen, Z. et al. Nuclear translocation of B-cell-specific transcription factor, BACH2, modulates ROS mediated cytotoxic responses in mantle cell lymphoma. PLoS ONE 8, e69126 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Kane, R. C. et al. Bortezomib for the treatment of mantle cell lymphoma. Clin. Cancer Res. 13, 5291–5294 (2007).

    Article  CAS  PubMed  Google Scholar 

  156. Denmeade, S. R. et al. Engineering a prostate-specific membrane antigen-activated tumor endothelial cell prodrug for cancer therapy. Sci. Transl. Med. 4, 140ra86 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Kardosh, A. et al. Aggravated endoplasmic reticulum stress as a basis for enhanced glioblastoma cell killing by bortezomib in combination with celecoxib or its non-coxib analogue, 2,5-dimethyl-celecoxib. Cancer Res. 68, 843–851 (2008).

    Article  CAS  PubMed  Google Scholar 

  158. Fribley, A., Zeng, Q. & Wang, C. Y. Proteasome inhibitor PS-341 induces apoptosis through induction of endoplasmic reticulum stress-reactive oxygen species in head and neck squamous cell carcinoma cells. Mol. Cell. Biol. 24, 9695–9704 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Tsutsumi, S. et al. Endoplasmic reticulum stress response is involved in nonsteroidal anti-inflammatory drug-induced apoptosis. Cell Death Differ. 11, 1009–1016 (2004).

    Article  CAS  PubMed  Google Scholar 

  160. Bernstein, W. B. & Dennis, P. A. Repositioning HIV protease inhibitors as cancer therapeutics. Curr. Opin. HIV AIDS 3, 666–675 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  161. Tai, D. J. et al. Changes in intracellular redox status influence multidrug resistance in gastric adenocarcinoma cells. Exp. Ther. Med. 4, 291–296 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Ryu, C. S. et al. Elevation of cysteine consumption in tamoxifen-resistant MCF-7 cells. Biochem. Pharmacol. 85, 197–206 (2012).

    Article  CAS  PubMed  Google Scholar 

  163. Griffith, O. W. Mechanism of action, metabolism, and toxicity of buthionine sulfoximine and its higher homologs, potent inhibitors of glutathione synthesis. J. Biol. Chem. 257, 13704–13712 (1982).

    CAS  PubMed  Google Scholar 

  164. Loganathan, S., Kandala, P. K., Gupta, P. & Srivastava, S. K. Inhibition of EGFR-AKT axis results in the suppression of ovarian tumors in vitro and in preclinical mouse model. PLoS ONE 7, e43577 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  166. Raj, L. et al. Selective killing of cancer cells by a small molecule targeting the stress response to ROS. Nature 475, 231–234 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Suarez-Almazor, M. E., Belseck, E., Shea, B., Wells, G. & Tugwell, P. Sulfasalazine for rheumatoid arthritis. Cochrane Database Syst Rev. 2009, CD000958 (2000).

    Google Scholar 

  168. Gout, P. W., Buckley, A. R., Simms, C. R. & Bruchovsky, N. Sulfasalazine, a potent suppressor of lymphoma growth by inhibition of the x(c)- cystine transporter: a new action for an old drug. Leukemia 15, 1633–1640 (2001).

    Article  CAS  PubMed  Google Scholar 

  169. Lo, M., Ling, V., Low, C., Wang, Y. Z. & Gout, P. W. Potential use of the anti-inflammatory drug, sulfasalazine, for targeted therapy of pancreatic cancer. Curr. Oncol. 17, 9–16 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Guan, J. et al. The xc- cystine/glutamate antiporter as a potential therapeutic target for small-cell lung cancer: use of sulfasalazine. Cancer Chemother. Pharmacol. 64, 463–472 (2009).

    Article  CAS  PubMed  Google Scholar 

  171. Montero, A. J. et al. Phase 2 study of neoadjuvant treatment with NOV-002 in combination with doxorubicin and cyclophosphamide followed by docetaxel in patients with HER-2 negative clinical stage II-IIIc breast cancer. Breast Cancer Res. Treat. 132, 215–223 (2012).

    Article  CAS  PubMed  Google Scholar 

  172. Townsend, D. M. et al. NOV-002, a glutathione disulfide mimetic, as a modulator of cellular redox balance. Cancer Res. 68, 2870–2877 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Sobhakumari, A. et al. Susceptibility of human head and neck cancer cells to combined inhibition of glutathione and thioredoxin metabolism. PLoS ONE 7, e48175 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Marzano, C. et al. Inhibition of thioredoxin reductase by auranofin induces apoptosis in cisplatin-resistant human ovarian cancer cells. Free Radic. Biol. Med. 42, 872–881 (2007).

    Article  CAS  PubMed  Google Scholar 

  175. Vaughn, A. E. & Deshmukh, M. Glucose metabolism inhibits apoptosis in neurons and cancer cells by redox inactivation of cytochrome c. Nature Cell Biol. 10, 1477–1483 (2008).

    Article  CAS  PubMed  Google Scholar 

  176. Polimeni, M. et al. Modulation of doxorubicin resistance by the glucose-6-phosphate dehydrogenase activity. Biochem. J. 439, 141–149 (2011).

    Article  CAS  PubMed  Google Scholar 

  177. Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Wang, J. B. et al. Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell 18, 207–219 (2010). This work underlines the importance of metabolic adaptation in cancer cells. It demonstrates that glutamine metabolism is crucial for cancer cell survival.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Le, A. et al. Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell. Metab. 15, 110–121 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Reinert, R. B. et al. Role of glutamine depletion in directing tissue-specific nutrient stress responses to l-asparaginase. J. Biol. Chem. 281, 31222–31233 (2006).

    Article  CAS  PubMed  Google Scholar 

  181. Dolma, S., Lessnick, S. L., Hahn, W. C. & Stockwell, B. R. Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. Cancer Cell 3, 285–296 (2003). This work demonstrates the potential of tailored therapeutic intervention against specific gene alterations in tumour cells.

    Article  CAS  PubMed  Google Scholar 

  182. Dixon, S. J. et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 1060–1072 (2012). This paper describes a new form of cell death that depends on iron.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Yagoda, N. et al. RAS–RAF–MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature 447, 864–868 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Shaw, A. T. et al. Selective killing of K-ras mutant cancer cells by small molecule inducers of oxidative stress. Proc. Natl Acad. Sci. USA 108, 8773–8778 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  185. Dang, L. et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739–744 (2009). This study elucidates the presence of a novel metabolic pathway induced by a tumour-specific gene alteration. The finding offers the opportunity to develop a tailored anticancer therapy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Sasaki, M. et al. D-2-hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function. Genes Dev. 26, 2038–2049 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Sasaki, M. et al. IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature 488, 656–659 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Losman, J. A. et al. (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science 339, 1621–1625 (2013).

    Article  CAS  PubMed  Google Scholar 

  189. Greenlee, H., Hershman, D. L. & Jacobson, J. S. Use of antioxidant supplements during breast cancer treatment: a comprehensive review. Breast Cancer Res. Treat. 115, 437–452 (2009).

    Article  CAS  PubMed  Google Scholar 

  190. Misale, S. et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature 486, 532–536 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Bell, E. L. & Chandel, N. S. Mitochondrial oxygen sensing: regulation of hypoxia-inducible factor by mitochondrial generated reactive oxygen species. Essays Biochem. 43, 17–27 (2007).

    Article  CAS  PubMed  Google Scholar 

  192. Chandel, N. S. et al. Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proc. Natl Acad. Sci. USA 95, 11715–11720 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Semenza, G. L. Oxygen sensing, homeostasis, and disease. N. Engl. J. Med. 365, 537–547 (2011).

    Article  CAS  PubMed  Google Scholar 

  194. Kincaid, M. M. & Cooper, A. A. ERADicate ER stress or die trying. Antioxid. Redox Signal. 9, 2373–2387 (2007).

    Article  CAS  PubMed  Google Scholar 

  195. Bravo, R. et al. Endoplasmic reticulum: ER stress regulates mitochondrial bioenergetics. Int. J. Biochem. Cell Biol. 44, 16–20 (2012).

    Article  CAS  PubMed  Google Scholar 

  196. Tanaka, H. et al. E2F1 and c-Myc potentiate apoptosis through inhibition of NF-κB activity that facilitates MnSOD-mediated ROS elimination. Mol. Cell 9, 1017–1029 (2002).

    Article  CAS  PubMed  Google Scholar 

  197. Irani, K. et al. Mitogenic signaling mediated by oxidants in Ras-transformed fibroblasts. Science 275, 1649–1652 (1997).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  199. Vafa, O. et al. c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate p53 function: a mechanism for oncogene-induced genetic instability. Mol Cell. 9, 1031–1044 (2002).

    Article  CAS  PubMed  Google Scholar 

  200. Li, W. & Kong, A. N. Molecular mechanisms of Nrf2-mediated antioxidant response. Mol. Carcinog. 48, 91–104 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Meister, A. Glutathione deficiency produced by inhibition of its synthesis, and its reversal; applications in research and therapy. Pharmacol. Ther. 51, 155–194 (1991).

    Article  CAS  PubMed  Google Scholar 

  202. Murphy, M. P. Mitochondrial thiols in antioxidant protection and redox signaling: distinct roles for glutathionylation and other thiol modifications. Antioxid. Redox Signal. 16, 476–495 (2012).

    Article  CAS  PubMed  Google Scholar 

  203. Vurusaner, B., Poli, G. & Basaga, H. Tumor suppressor genes and ROS: complex networks of interactions. Free Radic. Biol. Med. 52, 7–18 (2012).

    Article  CAS  PubMed  Google Scholar 

  204. Bouayed, J. & Bohn, T. Exogenous antioxidants — double-edged swords in cellular redox state: health beneficial effects at physiologic doses versus deleterious effects at high doses. Oxid. Med. Cell Longev. 3, 228–237 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  205. Wilson, J. X. Regulation of vitamin C transport. Annu. Rev. Nutr. 25, 105–125 (2005).

    Article  CAS  PubMed  Google Scholar 

  206. Brigelius-Flohe, R. & Traber, M. G. Vitamin E: function and metabolism. FASEB J. 13, 1145–1155 (1999).

    Article  CAS  PubMed  Google Scholar 

  207. Rayman, M. P. Selenium in cancer prevention: a review of the evidence and mechanism of action. Proc. Nutr. Soc. 64, 527–542 (2005).

    Article  CAS  PubMed  Google Scholar 

  208. Burton, G. W. & Ingold, K. U. β-carotene: an unusual type of lipid antioxidant. Science 224, 569–573 (1984).

    Article  CAS  PubMed  Google Scholar 

  209. Klaunig, J. E. & Kamendulis, L. M. The role of oxidative stress in carcinogenesis. Annu. Rev. Pharmacol. Toxicol. 44, 239–267 (2004).

    Article  CAS  PubMed  Google Scholar 

  210. Belfi, C. A., Chatterjee, S., Gosky, D. M., Berger, S. J. & Berger, N. A. Increased sensitivity of human colon cancer cells to DNA cross-linking agents after GRP78 up-regulation. Biochem. Biophys. Res. Commun. 257, 361–368 (1999).

    Article  CAS  PubMed  Google Scholar 

  211. Dufour, E. et al. Pancreatic tumor sensitivity to plasma L-asparagine starvation. Pancreas 41, 940–948 (2012).

    Article  CAS  PubMed  Google Scholar 

  212. Pieters, R. et al. L-asparaginase treatment in acute lymphoblastic leukemia: a focus on Erwinia asparaginase. Cancer 117, 238–249 (2011).

    Article  CAS  PubMed  Google Scholar 

  213. O'Dwyer, P. J. et al. Phase I trial of buthionine sulfoximine in combination with melphalan in patients with cancer. J. Clin. Oncol. 14, 249–256 (1996).

    Article  CAS  PubMed  Google Scholar 

  214. Lewis-Wambi, J. S. et al. Buthionine sulfoximine sensitizes antihormone-resistant human breast cancer cells to estrogen-induced apoptosis. Breast Cancer Res. 10, R104 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Zhu, J. et al. Using cyclooxygenase-2 inhibitors as molecular platforms to develop a new class of apoptosis-inducing agents. J. Natl Cancer Inst. 94, 1745–1757 (2002).

    Article  CAS  PubMed  Google Scholar 

  216. Gills, J. J. et al. Nelfinavir, a lead HIV protease inhibitor, is a broad-spectrum, anticancer agent that induces endoplasmic reticulum stress, autophagy, and apoptosis in vitro and in vivo. Clin. Cancer Res. 13, 5183–5194 (2007).

    Article  CAS  PubMed  Google Scholar 

  217. Simunek, T. et al. Anthracycline-induced cardiotoxicity: overview of studies examining the roles of oxidative stress and free cellular iron. Pharmacol. Rep. 61, 154–171 (2009).

    Article  CAS  PubMed  Google Scholar 

  218. The Alpha-Tocopherol Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N. Engl. J. Med. 330, 1029–1035 (1994).

  219. Omenn, G. S. et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N. Engl. J. Med. 334, 1150–1155 (1996).

    Article  CAS  PubMed  Google Scholar 

  220. Wang, F. et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 340, 622–626 (2013).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank members of the Mak laboratory, specifically D. Cescon for his valuable input and M. Saunders for her scientific editing. The authors acknowledge support from Canadian Institutes of Health Research (CIHR).

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  1. Isaac S. Harris

    Present address: Present address: Harvard Medical School, 240 Longwood Ave, Boston, Massachusetts 02115, USA.,

  2. Chiara Gorrini and Isaac S. Harris: These authors contributed equally to this work.

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  1. The Campbell Family Institute for Breast Cancer Research, University Health Network, 620 University Avenue, Toronto, M5G 2C1, Ontario, Canada

    Chiara Gorrini, Isaac S. Harris & Tak W. Mak

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Gorrini, C., Harris, I. & Mak, T. Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov 12, 931–947 (2013). https://doi.org/10.1038/nrd4002

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