Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach?

Nature Reviews Drug Discovery - Tập 8 Số 7 - Trang 579-591 - 2009
Dunyaporn Trachootham1, Jérôme Alexandre2, Peng Huang1
1Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
2Universite Paris Descartes, Assistance Publique – Hopitaux de Paris, EA1833, Hotel-Dieu, Service d'oncologie médicale, France

Tóm tắt

Từ khóa


Tài liệu tham khảo

Druker, B. J. et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N. Engl. J. Med. 355, 2408–2417 (2006).

Comoglio, P. M., Giordano, S. & Trusolino, L. Drug development of MET inhibitors: targeting oncogene addiction and expedience. Nature Rev. Drug Discov. 7, 504–516 (2008).

Couzin, J. Cancer drugs. Smart weapons prove tough to design. Science 298, 522–525 (2002).

Frantz, S. Drug discovery: playing dirty. Nature 437, 942–943 (2005).

Frantz, S. Drug approval triggers debate on future direction for cancer treatments. Nature Rev. Drug Discov. 5, 91 (2006).

Szatrowski, T. P. & Nathan, C. F. Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res. 51, 794–798 (1991).

Kawanishi, S., Hiraku, Y., Pinlaor, S. & Ma, N. Oxidative and nitrative DNA damage in animals and patients with inflammatory diseases in relation to inflammation-related carcinogenesis. Biol. Chem. 387, 365–372 (2006).

Toyokuni, S., Okamoto, K., Yodoi, J. & Hiai, H. Persistent oxidative stress in cancer. FEBS Lett. 358, 1–3 (1995).

Boonstra, J. & Post, J. A. Molecular events associated with reactive oxygen species and cell cycle progression in mammalian cells. Gene 337, 1–13 (2004).

Schafer, F. Q. & Buettner, G. R. Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. Free Radic Biol. Med. 30, 1191–1212 (2001).

Perry, G. et al. How important is oxidative damage? Lessons from Alzheimer's disease. Free Radic Biol. Med. 28, 831–834 (2000).

Behrend, L., Henderson, G. & Zwacka, R. M. Reactive oxygen species in oncogenic transformation. Biochem. Soc. Trans. 31, 1441–1444 (2003).

Wu, W. S. The signaling mechanism of ROS in tumor progression. Cancer Metastasis Rev. 25, 695–705 (2006).

Pelicano, H., Carney, D. & Huang, P. ROS stress in cancer cells and therapeutic implications. Drug Resist. Updat. 7, 97–110 (2004).

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

Pervaiz, S. & Clement, M. V. Tumor intracellular redox status and drug resistance — serendipity or a causal relationship? Curr. Pharm. Des 10, 1969–1977 (2004).

Tiligada, E. Chemotherapy: induction of stress responses. Endocr. Relat. Cancer 13 (Suppl. 1), S115–S124 (2006).

Sullivan, R. & Graham, C. H. Chemosensitization of cancer by nitric oxide. Curr. Pharm. Des. 14, 1113–1123 (2008).

Trachootham, D., Lu, W., Ogasawara, M. A., Nilsa, R. D. & Huang, P. Redox regulation of cell survival. Antioxid. Redox Signal. 10, 1343–1374 (2008).

Schneider, B. L. & Kulesz-Martin, M. Destructive cycles: the role of genomic instability and adaptation in carcinogenesis. Carcinogenesis 25, 2033–2044 (2004).

Martinez-Sanchez, G. & Giuliani, A. Cellular redox status regulates hypoxia inducible factor-1 activity. Role in tumour development. J. Exp. Clin. Cancer Res. 26, 39–50 (2007).

Chen, E. I. et al. Adaptation of energy metabolism in breast cancer brain metastases. Cancer Res. 67, 1472–1486 (2007).

Halliwell, B. Oxidative stress and cancer: have we moved forward? Biochem. J. 401, 1–11 (2007).

Swartz, H. M. & Gutierrez, P. L. Free radical increases in cancer: evidence that there is not a real increase. Science 198, 936–938 (1977).

Zhou, Y., Hileman, E. O., Plunkett, W., Keating, M. J. & Huang, P. Free radical stress in chronic lymphocytic leukemia cells and its role in cellular sensitivity to ROS-generating anticancer agents. Blood 101, 4098–4104 (2003).

Kamiguti, A. S. et al. Expression and activity of NOX5 in the circulating malignant B cells of hairy cell leukemia. J. Immunol. 175, 8424–8430 (2005).

Patel, B. P. et al. Lipid peroxidation, total antioxidant status, and total thiol levels predict overall survival in patients with oral squamous cell carcinoma. Integr. Cancer Ther. 6, 365–372 (2007).

Tsao, S. M., Yin, M. C. & Liu, W. H. Oxidant stress and B vitamins status in patients with non-small cell lung cancer. Nutr. Cancer 59, 8–13 (2007).

Kumar, B., Koul, S., Khandrika, L., Meacham, R. B. & Koul, H. K. Oxidative stress is inherent in prostate cancer cells and is required for aggressive phenotype. Cancer Res. 68, 1777–1785 (2008).

Oberley, T. D. & Oberley, L. W. Antioxidant enzyme levels in cancer. Histol. Histopathol. 12, 525–535 (1997).

Hu, Y. et al. Mitochondrial manganese-superoxide dismutase expression in ovarian cancer: role in cell proliferation and response to oxidative stress. J. Biol. Chem. 280, 39485–39492 (2005).

Saydam, N. et al. Determination of glutathione, glutathione reductase, glutathione peroxidase and glutathione S-transferase levels in human lung cancer tissues. Cancer Lett. 119, 13–19 (1997).

Murawaki, Y. et al. Aberrant expression of selenoproteins in the progression of colorectal cancer. Cancer Lett. 259, 218–230 (2008).

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

Rodrigues, M. S., Reddy, M. M. & Sattler, M. Cell cycle regulation by oncogenic tyrosine kinases in myeloid neoplasias: from molecular redox mechanisms to health implications. Antioxid. Redox Signal. 10, 1813–1848 (2008).

Brandon, M., Baldi, P. & Wallace, D. C. Mitochondrial mutations in cancer. Oncogene 25, 4647–4662 (2006).

Horn, H. F. & Vousden, K. H. Coping with stress: multiple ways to activate p53. Oncogene 26, 1306–1316 (2007).

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).

Kissil, J. L. et al. Requirement for Rac1 in a K-ras induced lung cancer in the mouse. Cancer Res. 67, 8089–8094 (2007).

Kopnin, P. B., Agapova, L. S., Kopnin, B. P. & Chumakov, P. M. Repression of sestrin family genes contributes to oncogenic Ras-induced reactive oxygen species up-regulation and genetic instability. Cancer Res. 67, 4671–4678 (2007).

Ishikawa, K. et al. ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis. Science 320, 661–664 (2008).

Indo, H. P. et al. Evidence of ROS generation by mitochondria in cells with impaired electron transport chain and mitochondrial DNA damage. Mitochondrion 7, 106–118 (2007).

Carew, J. S. et al. Mitochondrial DNA mutations in primary leukemia cells after chemotherapy: clinical significance and therapeutic implications. Leukemia 17, 1437–1447 (2003).

Van Houten, B., Woshner, V. & Santos, J. H. Role of mitochondrial DNA in toxic responses to oxidative stress. DNA Repair (Amst) 5, 145–152 (2006).

Achanta, G. & Huang, P. Role of p53 in sensing oxidative DNA damage in response to reactive oxygen species-generating agents. Cancer Res. 64, 6233–6239 (2004).

Zurer, I. et al. The role of p53 in base excision repair following genotoxic stress. Carcinogenesis 25, 11–19 (2004).

Achanta, G. et al. Novel role of p53 in maintaining mitochondrial genetic stability through interaction with DNA Pol gamma. EMBO J. 24, 3482–3492 (2005).

Sablina, A. A. et al. The antioxidant function of the p53 tumor suppressor. Nature Med. 11, 1306–1313 (2005).

Giorgio, M. et al. Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis. Cell 122, 221–233 (2005).

Rivera, A. & Maxwell, S. A. The p53-induced gene-6 (proline oxidase) mediates apoptosis through a calcineurin-dependent pathway. J. Biol. Chem. 280, 29346–29354 (2005).

Attardi, L. D. & Donehower, L. A. Probing p53 biological functions through the use of genetically engineered mouse models. Mutat. Res. 576, 4–21 (2005).

Vousden, K. H. & Lane, D. P. p53 in health and disease. Nature Rev. Mol. Cell Biol. 8, 275–283 (2007).

Bourdon, J. C. p53 and its isoforms in cancer. Br. J. Cancer 97, 277–282 (2007).

Azad, N., Rojanasakul, Y. & Vallyathan, V. Inflammation and lung cancer: roles of reactive oxygen/nitrogen species. J. Toxicol. Environ. Health B Crit. Rev. 11, 1–15 (2008).

Cook, J. A. et al. Oxidative stress, redox, and the tumor microenvironment. Semin. Radiat. Oncol. 14, 259–266 (2004).

Kundu, N., Zhang, S. & Fulton, A. M. Sublethal oxidative stress inhibits tumor cell adhesion and enhances experimental metastasis of murine mammary carcinoma. Clin. Exp. Metastasis 13, 16–22 (1995).

Fulton, A. M. & Chong, Y. C. The role of macrophage-derived TNFα in the induction of sublethal tumor cell DNA damage. Carcinogenesis 13, 77–81 (1992).

Karihtala, P. & Soini, Y. Reactive oxygen species and antioxidant mechanisms in human tissues and their relation to malignancies. Apmis 115, 81–103 (2007).

McEligot, A. J., Yang, S. & Meyskens, F. L. Jr. Redox regulation by intrinsic species and extrinsic nutrients in normal and cancer cells. Annu. Rev. Nutr. 25, 261–295 (2005).

Lu, W., Ogasawara, M. A. & Huang, P. Models of reactive oxygen species in cancer. Drug Discov. Today Dis. Models 4, 67–73 (2007).

Skrzydlewska, E. et al. Lipid peroxidation and antioxidant status in colorectal cancer. World J. Gastroenterol. 11, 403–406 (2005).

Ray, G. et al. Lipid peroxidation, free radical production and antioxidant status in breast cancer. Breast Cancer Res. Treat. 59, 163–170 (2000).

Skrzydlewska, E., Stankiewicz, A., Sulkowska, M., Sulkowski, S. & Kasacka, I. Antioxidant status and lipid peroxidation in colorectal cancer. J. Toxicol. Environ. Health A 64, 213–222 (2001).

Oltra, A. M., Carbonell, F., Tormos, C., Iradi, A. & Saez, G. T. Antioxidant enzyme activities and the production of MDA and 8-oxo-dG in chronic lymphocytic leukemia. Free Radic. Biol. Med. 30, 1286–1292 (2001).

Oberley, L. W. & Buettner, G. R. Role of superoxide dismutase in cancer: a review. Cancer Res. 39, 1141–1149 (1979).

Elchuri, S. et al. CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life. Oncogene 24, 367–380 (2005).

Lu, Y. P. et al. Enhanced skin carcinogenesis in transgenic mice with high expression of glutathione peroxidase or both glutathione peroxidase and superoxide dismutase. Cancer Res. 57, 1468–1474 (1997).

Egler, R. A. et al. Regulation of reactive oxygen species, DNA damage, and c-Myc function by peroxiredoxin 1. Oncogene 24, 8038–8050 (2005).

Skrzydlewska, E. et al. Antioxidant potential in esophageal, stomach and colorectal cancers. Hepatogastroenterology 50, 126–131 (2003).

Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

Clerkin, J. S., Naughton, R., Quiney, C. & Cotter, T. G. Mechanisms of ROS modulated cell survival during carcinogenesis. Cancer Lett. 266, 30–36 (2008).

Radisky, D. C. et al. Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature 436, 123–127 (2005).

Nishikawa, M. Reactive oxygen species in tumor metastasis. Cancer Lett. 266, 53–59 (2008).

Komatsu, D., Kato, M., Nakayama, J., Miyagawa, S. & Kamata, T. NADPH oxidase 1 plays a critical mediating role in oncogenic Ras-induced vascular endothelial growth factor expression. Oncogene 27, 4724–4732 (2008).

Ushio-Fukai, M. & Nakamura, Y. Reactive oxygen species and angiogenesis: NADPH oxidase as target for cancer therapy. Cancer Lett. 266, 37–52 (2008).

Ramsey, M. R. & Sharpless, N. E. ROS as a tumour suppressor? Nature Cell Biol. 8, 1213–1215 (2006).

Takahashi, A. et al. Mitogenic signalling and the p16INK4a-Rb pathway cooperate to enforce irreversible cellular senescence. Nature Cell Biol. 8, 1291–1297 (2006).

Fruehauf, J. P. & Meyskens, F. L. Jr. Reactive oxygen species: a breath of life or death? Clin. Cancer Res. 13, 789–794 (2007).

Choi, J., Liu, R. M. & Forman, H. J. Adaptation to oxidative stress: quinone-mediated protection of signaling in rat lung epithelial L2 cells. Biochem. Pharmacol. 53, 987–993 (1997).

Kim, G. J., Chandrasekaran, K. & Morgan, W. F. Mitochondrial dysfunction, persistently elevated levels of reactive oxygen species and radiation-induced genomic instability: a review. Mutagenesis 21, 361–367 (2006).

Ogasawara, M. A. & Zhang, H. Redox regulation and its emerging roles in stem cells and stem-like cancer cells. Antioxid. Redox Signal. (2008).

Irmak, M. B., Ince, G., Ozturk, M. & Cetin-Atalay, R. Acquired tolerance of hepatocellular carcinoma cells to selenium deficiency: a selective survival mechanism? Cancer Res. 63, 6707–6715 (2003).

Young, T. W. et al. Activation of antioxidant pathways in ras-mediated oncogenic transformation of human surface ovarian epithelial cells revealed by functional proteomics and mass spectrometry. Cancer Res. 64, 4577–4584 (2004).

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

Benassi, B. et al. c-Myc phosphorylation is required for cellular response to oxidative stress. Mol. Cell 21, 509–519 (2006).

Vogel, A. et al. Sustained phosphorylation of Bid is a marker for resistance to Fas-induced apoptosis during chronic liver diseases. Gastroenterology 130, 104–119 (2006).

Kim, G. J., Chandrasekaran, K. & Morgan, W. F. Mitochondrial dysfunction, persistently elevated levels of reactive oxygen species and radiation-induced genomic instability: a review. Mutagenesis 21, 361–367 (2006).

Wallace, D. C. The mitochondrial genome in human adaptive radiation and disease: on the road to therapeutics and performance enhancement. Gene 354, 169–180 (2005).

Xia, C. et al. Reactive oxygen species regulate angiogenesis and tumor growth through vascular endothelial growth factor. Cancer Res. 67, 10823–10830 (2007).

Kondoh, H., Lleonart, M. E., Bernard, D. & Gil, J. Protection from oxidative stress by enhanced glycolysis; a possible mechanism of cellular immortalization. Histol. Histopathol. 22, 85–90 (2007).

Townsend, D. M. & Tew, K. D. The role of glutathione-S-transferase in anti-cancer drug resistance. Oncogene 22, 7369–7375 (2003).

Yadav, S., Zajac, E., Singhal, S. S. & Awasthi, S. Linking stress-signaling, glutathione metabolism, signaling pathways and xenobiotic transporters. Cancer Metastasis Rev. 26, 59–69 (2007).

Kong, Q. & Lillehei, K. O. Antioxidant inhibitors for cancer therapy. Med. Hypotheses 51, 405–409 (1998).

Kong, Q., Beel, J. A. & Lillehei, K. O. A threshold concept for cancer therapy. Med. Hypotheses 55, 29–35 (2000).

Cabello, C. M., Bair, W. B. 3rd & Wondrak, G. T. Experimental therapeutics: targeting the redox Achilles heel of cancer. Curr. Opin. Investig. Drugs 8, 1022–1037 (2007).

Fry, F. H. & Jacob, C. Sensor/effector drug design with potential relevance to cancer. Curr. Pharm. Des 12, 4479–4499 (2006).

Niu, C. et al. Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients. Blood 94, 3315–3324 (1999).

Soignet, S. L. et al. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N. Engl. J. Med. 339, 1341–1348 (1998).

Ramanathan, B. et al. Resistance to paclitaxel is proportional to cellular total antioxidant capacity. Cancer Res. 65, 8455–8460 (2005).

Attia, S. et al. A phase 2 consortium (P2C) trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) for advanced adenocarcinoma of the pancreas. Invest. New Drugs 26, 369–379 (2008).

Hour, T. C. et al. Characterization of molecular events in a series of bladder urothelial carcinoma cell lines with progressive resistance to arsenic trioxide. Anticancer Drugs 15, 779–785 (2004).

Adam-Vizi, V. & Chinopoulos, C. Bioenergetics and the formation of mitochondrial reactive oxygen species. Trends Pharmacol. Sci. 27, 639–645 (2006).

Pelicano, H. et al. Inhibition of mitochondrial respiration: a novel strategy to enhance drug-induced apoptosis in human leukemia cells by a reactive oxygen species-mediated mechanism. J. Biol. Chem. 278, 37832–37839 (2003).

Myers, C. E. et al. Adriamycin: the role of lipid peroxidation in cardiac toxicity and tumor response. Science 197, 165–167 (1977).

Wondrak, G. T. NQO1-activated phenothiazinium redox cyclers for the targeted bioreductive induction of cancer cell apoptosis. Free Radic. Biol. Med. 43, 178–190 (2007).

Magda, D. & Miller, R. A. Motexafin gadolinium: a novel redox active drug for cancer therapy. Semin. Cancer Biol. 16, 466–476 (2006).

Vasquez-Vivar, J. et al. Endothelial nitric oxide synthase-dependent superoxide generation from adriamycin. Biochemistry 36, 11293–11297 (1997).

Kotamraju, S., Chitambar, C. R., Kalivendi, S. V., Joseph, J. & Kalyanaraman, B. Transferrin receptor-dependent iron uptake is responsible for doxorubicin-mediated apoptosis in endothelial cells: role of oxidant-induced iron signaling in apoptosis. J. Biol. Chem. 277, 17179–17187 (2002).

Whitnall, M., Howard, J., Ponka, P. & Richardson, D. R. A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics. Proc. Natl Acad. Sci. USA 103, 14901–14906 (2006).

Finch, R. A. et al. Triapine (3-aminopyridine-2-carboxaldehyde- thiosemicarbazone): A potent inhibitor of ribonucleotide reductase activity with broad spectrum antitumor activity. Biochem. Pharmacol. 59, 983–991 (2000).

Tominaga, K. et al. Evidence for cancer-associated expression of NADPH oxidase 1 (Nox1)-based oxidase system in the human stomach. Free Radic. Biol. Med. 43, 1627–1638 (2007).

Kim, H. J., Oridate, N. & Lotan, R. Increased level of the p67phox subunit of NADPH oxidase by 4HPR in head and neck squamous carcinoma cells. Int. J. Oncol. 27, 787–790 (2005).

Tuma, R. S. Reactive oxygen species may have antitumor activity in metastatic melanoma. J. Natl Cancer Inst. 100, 11–12 (2008).

Kirshner, J. R. et al. Elesclomol induces cancer cell apoptosis through oxidative stress. Mol. Cancer Ther. 7, 2319–2327 (2008).

Dvorakova, K. et al. Induction of oxidative stress and apoptosis in myeloma cells by the aziridine-containing agent imexon. Biochem. Pharmacol. 60, 749–758 (2000).

Xu, K. & Thornalley, P. J. Involvement of glutathione metabolism in the cytotoxicity of the phenethyl isothiocyanate and its cysteine conjugate to human leukaemia cells in vitro. Biochem. Pharmacol. 61, 165–177 (2001).

Zhang, Y. & Talalay, P. Anticarcinogenic activities of organic isothiocyanates: chemistry and mechanisms. Cancer Res. 54, 1976–1981 (1994).

Griffith, O. W. & Meister, A. Potent and specific inhibition of glutathione synthesis by buthionine sulfoximine (S-n-butyl homocysteine sulfoximine). J. Biol. Chem. 254, 7558–7560 (1979).

Lo, M., Wang, Y. Z. & Gout, P. W. The x(c)- cystine/glutamate antiporter: a potential target for therapy of cancer and other diseases. J. Cell Physiol. 215, 593–602 (2008).

Ceccarelli, J. et al. The redox state of the lung cancer microenvironment depends on the levels of thioredoxin expressed by tumor cells and affects tumor progression and response to prooxidants. Int. J. Cancer 123, 1770–1778 (2008).

Kaimul, A. M., Nakamura, H., Masutani, H. & Yodoi, J. Thioredoxin and thioredoxin-binding protein-2 in cancer and metabolic syndrome. Free Radic. Biol. Med. 43, 861–868 (2007).

Kirkpatrick, D. L., Ehrmantraut, G., Stettner, S., Kunkel, M. & Powis, G. Redox active disulfides: the thioredoxin system as a drug target. Oncol. Res. 9, 351–356 (1997).

Welsh, S. J. et al. The thioredoxin redox inhibitors 1-methylpropyl 2-imidazolyl disulfide and pleurotin inhibit hypoxia-induced factor 1alpha and vascular endothelial growth factor formation. Mol. Cancer Ther. 2, 235–243 (2003).

Huang, P., Feng, L., Oldham, E. A., Keating, M. J. & Plunkett, W. Superoxide dismutase as a target for the selective killing of cancer cells. Nature 407, 390–395 (2000).

Juarez, J. C. et al. Copper binding by tetrathiomolybdate attenuates angiogenesis and tumor cell proliferation through the inhibition of superoxide dismutase 1. Clin. Cancer Res. 12, 4974–4982 (2006).

Smith, P. S., Zhao, W., Spitz, D. R. & Robbins, M. E. Inhibiting catalase activity sensitizes 36B10 rat glioma cells to oxidative stress. Free Radic. Biol. Med. 42, 787–797 (2007).

Fang, J., Sawa, T., Akaike, T., Greish, K. & Maeda, H. Enhancement of chemotherapeutic response of tumor cells by a heme oxygenase inhibitor, pegylated zinc protoporphyrin. Int. J. Cancer 109, 1–8 (2004).

Lenehan, P. F. et al. Resistance to oxidants associated with elevated catalase activity in HL-60 leukemia cells that overexpress multidrug-resistance protein does not contribute to the resistance to daunorubicin manifested by these cells. Cancer Chemother. Pharmacol. 35, 377–386 (1995).

Zhou, P., Kalakonda, N. & Comenzo, R. L. Changes in gene expression profiles of multiple myeloma cells induced by arsenic trioxide (ATO): possible mechanisms to explain ATO resistance in vivo. Br. J. Haematol. 128, 636–644 (2005).

Hoshida, Y. et al. Gene expressions associated with chemosensitivity in human hepatoma cells. Hepatogastroenterology 54, 489–492 (2007).

Trachootham, D. et al. Effective elimination of fludarabine-resistant CLL cells by PEITC through a redox-mediated mechanism. Blood 112, 1912–1922 (2008).

Zhang, H. et al. Effective killing of Gleevec-resistant CML cells with T315I mutation by a natural compound PEITC through redox-mediated mechanism. Leukemia 22, 1191–1199 (2008).

Bahlis, N. J. et al. Feasibility and correlates of arsenic trioxide combined with ascorbic acid-mediated depletion of intracellular glutathione for the treatment of relapsed/refractory multiple myeloma. Clin. Cancer Res. 8, 3658–3668 (2002).

Lee, H. R. et al. Adaptive response to GSH depletion and resistance to L-buthionine-(S, R)-sulfoximine: involvement of Nrf2 activation. Mol. Cell Biochem. 318, 23–31 (2008).

Kang, M. H., Wan, Z., Kang, Y. H., Sposto, R. & Reynolds, C. P. Mechanism of synergy of N-(4-hydroxyphenyl)retinamide and ABT-737 in acute lymphoblastic leukemia cell lines: Mcl-1 inactivation. J. Natl Cancer Inst. 100, 580–595 (2008).

Ma, B. et al. A multicenter phase II trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine) and gemcitabine in advanced non-small-cell lung cancer with pharmacokinetic evaluation using peripheral blood mononuclear cells. Invest. New Drugs 26, 169–173 (2008).

Engel, R. H. & Evens, A. M. Oxidative stress and apoptosis: a new treatment paradigm in cancer. Front. Biosci. 11, 300–312 (2006).

Visvader, J. E. & Lindeman, G. J. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nature Rev. Cancer 8, 755–768 (2008).

Eyler, C. E. & Rich, J. N. Survival of the fittest: cancer stem cells in therapeutic resistance and angiogenesis. J. Clin. Oncol. 26, 2839–2845 (2008).

Li, X. et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J. Natl Cancer Inst. 100, 672–679 (2008).

Bao, S. et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444, 756–760 (2006).

Jang, Y. Y. & Sharkis, S. J. A low level of reactive oxygen species selects for primitive hematopoietic stem cells that may reside in the low-oxygenic niche. Blood 110, 3056–3063 (2007).

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

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

Tothova, Z. et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128, 325–339 (2007).

Naka, K., Muraguchi, T., Hoshii, T. & Hirao, A. Regulation of reactive oxygen species and genomic stability in hematopoietic stem cells. Antioxid. Redox Signal. (2008).

Toyokuni, S. Novel aspects of oxidative stress-associated carcinogenesis. Antioxid. Redox Signal. 8, 1373–1377 (2006).

Ghaffari, S. Oxidative stress in the regulation of normal and neoplastic hematopoiesis. Antioxid. Redox Signal. 10, 1923–1940 (2008).

Phillips, T. M., McBride, W. H. & Pajonk, F. The response of CD24(-/low)/CD44+ breast cancer-initiating cells to radiation. J. Natl Cancer Inst. 98, 1777–1785 (2006).

Simon, M. C. & Keith, B. The role of oxygen availability in embryonic development and stem cell function. Nature Rev. Mol. Cell Biol. 9, 285–296 (2008).

Wang, J. & Yi, J. Cancer cell killing via ROS: to increase or decrease, that is the question. Cancer Biol. Ther. 7, 1875–1884 (2008).

Bjelakovic, G., Nikolova, D., Gluud, L. L., Simonetti, R. G. & Gluud, C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. Jama 297, 842–857 (2007).

Halliwell, B. The antioxidant paradox. Lancet 355, 1179–1180 (2000).

Alexandre, J. et al. Accumulation of hydrogen peroxide is an early and crucial step for paclitaxel-induced cancer cell death both in vitro and in vivo. Int. J. Cancer 119, 41–48 (2006).

Llobet, D. et al. Antioxidants block proteasome inhibitor function in endometrial carcinoma cells. Anticancer Drugs 19, 115–124 (2008).

Bairati, I. et al. Randomized trial of antioxidant vitamins to prevent acute adverse effects of radiation therapy in head and neck cancer patients. J. Clin. Oncol. 23, 5805–5813 (2005).

Bey, E. A. et al. An NQO1- and PARP-1-mediated cell death pathway induced in non-small-cell lung cancer cells by beta-lapachone. Proc. Natl Acad. Sci. USA 104, 11832–11837 (2007).

Guzman, M. L. et al. Rapid and selective death of leukemia stem and progenitor cells induced by the compound 4-benzyl, 2-methyl, 1, 2, 4-thiadiazolidine, 3, 5 dione (TDZD-8). Blood 110, 4436–4444 (2007).

Maeda, H. et al. Effective treatment of advanced solid tumors by the combination of arsenic trioxide and L-buthionine-sulfoximine. Cell Death Differ. 11, 737–746 (2004).

Dragovich, T. et al. Phase I trial of imexon in patients with advanced malignancy. J. Clin. Oncol. 25, 1779–1784 (2007).

Alexandre, J. et al. Improvement of the therapeutic index of anticancer drugs by the superoxide dismutase mimic mangafodipir. J. Natl Cancer Inst. 98, 236–244 (2006).

Juarez, J. C. et al. Superoxide dismutase 1 (SOD1) is essential for H2O2-mediated oxidation and inactivation of phosphatases in growth factor signaling. Proc. Natl Acad. Sci. USA 105, 7147–7152 (2008).

Lu, J., Chew, E. H. & Holmgren, A. Targeting thioredoxin reductase is a basis for cancer therapy by arsenic trioxide. Proc. Natl Acad. Sci. USA 104, 12288–12293 (2007).