Modulation of oxidative stress as an anticancer strategy

Nature Reviews Drug Discovery

Volumn 12, Issue 12, 2013, Pages 931-947

  Gorrini, Chiara ^a   Harris, Isaac S ^a,b   Mak, Tak W ^a  

^a PRINCESS MARGARET HOSPITAL   (Canada)

^b HARVARD MEDICAL SCHOOL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA TOCOPHEROL; ARSENIC TRIOXIDE; ASCORBIC ACID; BETA CAROTENE; CARBOPLATIN; CHOLINE; CISPLATIN; CURCUMIN; DNA; DOCETAXEL; DOXORUBICIN; EPIGALLOCATECHIN GALLATE; FLUOROURACIL; FOLIC ACID ANTAGONIST; GENISTEIN; OXALIPLATIN; PACLITAXEL; PIPERINE; PROTEIN P53; RAPAMYCIN; REACTIVE OXYGEN METABOLITE; RETINOL; SULFORAPHANE; TANESPIMYCIN; THEANINE; TRANSCRIPTION FACTOR FOXO; UNINDEXED DRUG; VINBLASTINE; VINCRISTINE; VITAMIN D;

AMINO ACID METABOLISM; BRAIN TUMOR; BREAST TUMOR; CANCER CELL; CANCER CHEMOTHERAPY; CARCINOGENESIS; COLON CANCER; DIETARY INTAKE; DRUG MECHANISM; ENDOPLASMIC RETICULUM STRESS; GENE MUTATION; GENOTYPE; GLUTATHIONE METABOLISM; HEAD AND NECK CANCER; HUMAN; IONIZING RADIATION; NEOPLASM; NONHUMAN; ONCOGENE; OXIDATION REDUCTION STATE; OXIDATIVE STRESS; PANCREAS TUMOR; PRIORITY JOURNAL; PROMYELOCYTIC LEUKEMIA; RECTUM CANCER; REGULATORY MECHANISM; REVIEW; SIGNAL TRANSDUCTION; TUMOR SUPPRESSOR GENE;

ANIMALS; ANTINEOPLASTIC AGENTS; HUMANS; NEOPLASMS; OXIDATIVE STRESS; REACTIVE OXYGEN SPECIES;

EID: 84889575198     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd4002     Document Type: Review

References (220)

1. Cairns, R. A., Harris, I. S. & Mak, T. W. Regulation of cancer cell metabolism. Nature Rev. Cancer 11, 85-95 (2011
2. Diehn, M. et al. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 458, 780-783 (2009
3. Weinstein, I. B. & Joe, A. Oncogene addiction. Cancer Res. 68, 3077-3080 (2008
4. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: The next generation. Cell 144, 646-674 (2011
5. Jones, R. G. & Thompson, C. B. Tumor suppressors and cell metabolism: A recipe for cancer growth. Genes Dev. 23, 537-548 (2009
6. Finkel, T. Signal transduction by mitochondrial oxidants. J. Biol. Chem. 287, 4434-4440 (2012
7. Handy, D. E. & Loscalzo, J. Redox regulation of mitochondrial function. Antioxid. Redox Signal. 16, 1323-1367 (2012
8. Schrader, M. & Fahimi, H. D. Peroxisomes and oxidative stress. Biochim. Biophys. Acta 1763, 1755-1766 (2006
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
10. Sena, L. A. & Chandel, N. S. Physiological roles of mitochondrial reactive oxygen species. Mol. Cell 48, 158-167 (2012
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
12. Rhee, S. G. H2O2, a necessary evil for cell signaling. Science 312, 1882-1883 (2006
13. Naik, E. & Dixit, V. M. Mitochondrial reactive oxygen species drive proinflammatory cytokine production. J. Exp. Med. 208, 417-420 (2011
14. Gloire, G., Legrand-Poels, S. & Piette, J. NF κB activation by reactive oxygen species: Fifteen years later. Biochem. Pharmacol. 72, 1493-1505 (2006
15. Oberley, L. W. Free radicals and diabetes. Free Radic. Biol. Med. 5, 113-124 (1988
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
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
18. Martindale, J. L. & Holbrook, N. J. Cellular response to oxidative stress: Signaling for suicide and survival. J. Cell. Physiol. 192, 1-15 (2002
19. Leslie, N. R. et al. Redox regulation of PI 3 kinase signalling via inactivation of PTEN. EMBO J. 22, 5501-5510 (2003
20. Xu, D., Rovira, I. I. & Finkel, T. Oxidants painting the cysteine chapel: Redox regulation of PTPs. Dev. Cell 2, 251-252 (2002
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
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
24. Schafer, Z. T. et al. Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment. Nature 461, 109-113 (2009
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
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
27. Meister, A. Selective modification of glutathione metabolism. Science 220, 472-477 (1983
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
29. Mandal, P. K. et al. System x(c)- and thioredoxin reductase 1 cooperatively rescue glutathione deficiency. J. Biol. Chem. 285, 22244-22253 (2010
30. Johansson, L., Gafvelin, G. & Arner, E. S. Selenocysteine in proteins - properties and biotechnological use. Biochim. Biophys. Acta 1726, 1-13 (2005
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
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
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
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
35. Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807-1812 (2008
36. Mardis, E. R. et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N. Engl. J. Med. 361, 1058-1066 (2009
37. Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765-773 (2009
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
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
40. Mitsuishi, Y. et al. Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell 22, 66-79 (2012
41. Arner, E. S. & Holmgren, A. Physiological functions of thioredoxin and thioredoxin reductase. Eur. J. Biochem. 267, 6102-6109 (2000
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
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
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
45. Gozzelino, R., Jeney, V. & Soares, M. P. Mechanisms of cell protection by heme oxygenase 1. Annu. Rev. Pharmacol. Toxicol. 50, 323-354 (2010
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
47. Orino, K. et al. Ferritin and the response to oxidative stress. Biochem. J. 357, 241-247 (2001
48. Weinberg, E. D. The role of iron in cancer. Eur. J. Cancer Prev. 5, 19-36 (1996
49. Kops, G J. et al. Direct control of the Forkhead transcription factor AFX by protein kinase B. Nature 398, 630-634 (1999
50. Brunet, A. et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96, 857-868 (1999
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
52. Greer, E. L. & Brunet, A. FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene 24, 7410-7425 (2005
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
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
55. Nemoto, S. & Finkel, T. Redox regulation of forkhead proteins through a p66shc dependent signaling pathway. Science 295, 2450-2452 (2002
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
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
58. Cheng, Z. et al. Foxo1 integrates insulin signaling with mitochondrial function in the liver. Nature Med. 15, 1307-1311 (2009
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
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
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
62. Kops, G. J. et al. Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature 419, 316-321 (2002
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
64. Vousden, K. H. & Ryan, K. M. p53 and metabolism. Nature Rev. Cancer 9, 691-700 (2009
65. Bensaad, K. et al. TIGAR, a p53 inducible regulator of glycolysis and apoptosis. Cell 126, 107-120 (2006
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
67. Gao, P. et al. c Myc suppression of miR 23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458, 762-765 (2009
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
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
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
71. Pinnix, Z. K. et al. Ferroportin and iron regulation in breast cancer progression and prognosis. Sci. Transl. Med. 2, 43ra56 (2010
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
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
74. Frezza, C. et al. Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase. Nature 477, 225-228 (2011
75. DeNicola, G. M. et al. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 475, 106-109 (2011
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
77. Kim, R. H. et al. DJ 1, a novel regulator of the tumor suppressor PTEN. Cancer Cell 7, 263-273 (2005
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
79. Vasseur, S. et al. Consequences of DJ 1 upregulation following p53 loss and cell transformation. Oncogene 31, 664-670 (2012
80. Lee, J. & Wolfgang, M. J. Metabolomic profiling reveals a role for CPT1c in neuronal oxidative metabolism. BMC Biochem. 13, 23 (2012
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
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
83. Kim, Y. R. et al. Oncogenic NRF2 mutations in squamous cell carcinomas of oesophagus and skin. J. Pathol. 220, 446-451 (2010
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
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
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
87. Naka, K. et al. TGF-β-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature 463, 676-680 (2010
88. Sykes, S. M. et al. AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias. Cell 146, 697-708 (2011
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
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
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
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
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
94. Bae, I. et al. BRCA1 induces antioxidant gene expression and resistance to oxidative stress. Cancer Res. 64, 7893-7909 (2004
95. Saha, T., Rih, J. K. & Rosen, E. M. BRCA1 down-regulates cellular levels of reactive oxygen species. FEBS Lett. 583, 1535-1543 (2009
96. Gorrini, C. et al. BRCA1 interacts with Nrf2 to regulate antioxidant signaling and cell survival. J. Exp. Med. 210, 1529-1544 (2013
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
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
99. Guo, Z., Kozlov, S., Lavin, M. F., Person, M. D. & Paull, T. T. ATM activation by oxidative stress. Science. 330, 517-521 (2010
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
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
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
103. Sullivan, L. B. et al. The proto-oncometabolite fumarate binds glutathione to amplify ROS-dependent signaling. Mol. Cell 51, 236-248 (2013
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
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
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
107. Vander Heiden, M. G. et al. Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Science 329, 1492-1499 (2010
108. Anastasiou, D. et al. Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to antioxidant responses. Science 334, 1278-1283 (2011
109. Locasale, J. W. et al. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nature Genet. 43, 869-874 (2011
110. Possemato, R. et al. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature 476, 346-350 (2011
111. Jain, M. et al. Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science 336, 1040-1044 (2012
112. Chaneton, B. et al. Serine is a natural ligand and allosteric activator of pyruvate kinase M2. Nature 491, 458-462 (2012
113. Goodison, S., Urquidi, V. & Tarin, D. CD44 cell adhesion molecules. Mol. Pathol. 52, 189-196 (1999
114. Zoller, M. CD44: Can a cancer-initiating cell profit from an abundantly expressed molecule? Nature Rev. Cancer 11, 254-267 (2011
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
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
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
118. Hurst, R. et al. Selenium and prostate cancer: Systematic review and meta-analysis. Am. J. Clin. Nutr. 96, 111-122 (2012
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
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
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
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
123. Conklin, K. A. Chemotherapy-associated oxidative stress: Impact on chemotherapeutic effectiveness. Integr. Cancer Ther. 3, 294-300 (2004
124. Barrera, G. Oxidative stress and lipid peroxidation products in cancer progression and therapy. ISRN Oncol. 2012, 137289 (2012
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
126. Kaufmann, S. H. & Earnshaw, W. C. Induction of apoptosis by cancer chemotherapy. Exp. Cell Res. 256, 42-49 (2000
127. Miller, W. H. et al. Mechanisms of action of arsenic trioxide. Cancer Res. 62, 3893-3903 (2002
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
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
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
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
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
133. Kachadourian, R. et al. 2 methoxyestradiol does not inhibit superoxide dismutase. Arch. Biochem. Biophys. 392, 349-353 (2001
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
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
136. Neckers, L. & Workman, P. Hsp90 molecular chaperone inhibitors: Are we there yet? Clin. Cancer Res. 18, 64-76 (2012
137. Hao, H. et al. HSP90 and its inhibitors. Oncol. Rep. 23, 1483-1492 (2010
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
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
140. Metzger-Filho, O. et al. Dissecting the heterogeneity of triple-negative breast cancer. J. Clin. Oncol. 30, 1879-1887 (2012
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
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
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
144. Kummar, S. et al. Advances in using PARP inhibitors to treat cancer. BMC Med. 10, 25 (2012
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
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
147. Michels, J. et al. Cisplatin resistance associated with PARP hyperactivation. Cancer Res. 73, 2271-2280 (2013
148. Michels, J. et al. Synergistic interaction between cisplatin and PARP inhibitors in non-small cell lung cancer. Cell Cycle 12, 877-883 (2013
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
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
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
152. Joazeiro, C. A., Anderson, K. C. & Hunter, T. Proteasome inhibitor drugs on the rise. Cancer Res. 66, 7840-7842 (2006
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
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
155. Kane, R. C. et al. Bortezomib for the treatment of mantle cell lymphoma. Clin. Cancer Res. 13, 5291-5294 (2007
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
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
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
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
160. Bernstein, W. B. & Dennis, P. A. Repositioning HIV protease inhibitors as cancer therapeutics. Curr. Opin. HIV AIDS 3, 666-675 (2008
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
162. Ryu, C. S. et al. Elevation of cysteine consumption in tamoxifen-resistant MCF 7 cells. Biochem. Pharmacol. 85, 197-206 (2012
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
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
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
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
167. Suarez-Almazor, M. E., Belseck, E., Shea, B., Wells, G. & Tugwell, P. Sulfasalazine for rheumatoid arthritis. Cochrane Database Syst Rev. 2009, CD000958 (2000
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
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
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
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
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
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
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
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
176. Polimeni, M. et al. Modulation of doxorubicin resistance by the glucose-6 phosphate dehydrogenase activity. Biochem. J. 439, 141-149 (2011
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
178. Wang, J. B. et al. Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell 18, 207-219 (2010
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
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
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
182. Dixon, S. J. et al. Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell 149, 1060-1072 (2012
183. Yagoda, N. et al. RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature 447, 864-868 (2007
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
185. Dang, L. et al. Cancer-associated IDH1 mutations produce 2 hydroxyglutarate. Nature 462, 739-744 (2009
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
187. Sasaki, M. et al. IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature 488, 656-659 (2012
188. Losman, J. A. et al. (R)-2 hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science 339, 1621-1625 (2013
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
190. Misale, S. et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature 486, 532-536 (2012
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
192. Chandel, N. S. et al. Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proc. Natl Acad. Sci. USA 95, 11715-11720 (1998
193. Semenza, G. L. Oxygen sensing, homeostasis, and disease. N. Engl. J. Med. 365, 537-547 (2011
194. Kincaid, M. M. & Cooper, A. A. ERADicate ER stress or die trying. Antioxid. Redox Signal. 9, 2373-2387 (2007
195. Bravo, R. et al. Endoplasmic reticulum: ER stress regulates mitochondrial bioenergetics. Int. J. Biochem. Cell Biol. 44, 16-20 (2012
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
197. Irani, K. et al. Mitogenic signaling mediated by oxidants in Ras-transformed fibroblasts. Science 275, 1649-1652 (1997
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
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
200. Li, W. & Kong, A. N. Molecular mechanisms of Nrf2 mediated antioxidant response. Mol. Carcinog. 48, 91-104 (2009
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
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
203. Vurusaner, B., Poli, G. & Basaga, H. Tumor suppressor genes and ROS: Complex networks of interactions. Free Radic. Biol. Med. 52, 7-18 (2012
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
205. Wilson, J. X. Regulation of vitamin C transport. Annu. Rev. Nutr. 25, 105-125 (2005
206. Brigelius-Flohe, R. & Traber, M. G. Vitamin E: Function and metabolism. FASEB J. 13, 1145-1155 (1999
207. Rayman, M. P. Selenium in cancer prevention: A review of the evidence and mechanism of action. Proc. Nutr. Soc. 64, 527-542 (2005
208. Burton, G. W. & Ingold, K. U. β-carotene: An unusual type of lipid antioxidant. Science 224, 569-573 (1984
209. Klaunig, J. E. & Kamendulis, L. M. The role of oxidative stress in carcinogenesis. Annu. Rev. Pharmacol. Toxicol. 44, 239-267 (2004
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
211. Dufour, E. et al. Pancreatic tumor sensitivity to plasma l asparagine starvation. Pancreas 41, 940-948 (2012
212. Pieters, R. et al. l asparaginase treatment in acute lymphoblastic leukemia: A focus on Erwinia asparaginase. Cancer 117, 238-249 (2011
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
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
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
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
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
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
220. Wang, F. et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 340, 622-626 (2013