Targeting the Antioxidant Enzymes to Enhance the Efficacy of Chemotherapy
Abstract
The major obstacle for failure of cancer treatment is the therapy resistance. As cancer cells have several mechanisms of cellular adaptation to survive and evade the body mechanism and counteract the cytotoxic attack of chemotherapy. One of the remarkable adaptation mechanisms is an augmentation in antioxidant enzyme levels within the cancer cells including NAD(P)H:quinone oxidase 1 (NQO1), heme oxygenase-1 (HO-1) and g-glutamylcysteine ligase (g-GCL). This adaptation renders the cancer cells not only to survive in oxidative stress condition that higher than in normal cells but also protects cancer cells from various insults condition as well as chemotherapeutic agents. Inhibition of these enzymes together with chemotherapeutic agents has been found to improve the efficacy of chemotherapeutic agents. Thus, the suppression of antioxidant enzymes within the cell in combination with chemotherapeutic treatment might be a new strategy to overcome chemotherapy resistance in cancer.Keywords: antioxidant enzymes, chemotherapeutic agents, cancerReferences
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Ames, B.N., Shigenaga, M.K. & Hagen, T.M. (1993). Oxidants, antioxidants, and the degenerative diseases of aging. Proceedings of the National Academy of Sciences of the United States of America, 90(17), 7915-22.
Awadallah, N.S., Dehn, D., Shah, R.J., Russell Nash, S., Chen, Y.K., Ross, D., Bentz, J.S. & Shroyer, K.R. (2008). NQO1 expression in pancreatic cancer and its potential use as a biomarker. Applied Immunohistochemistry & Molecular Morphology, 16(1), 24-31.
Begleiter, A. & Fourie, J. (2004). Induction of NQO1 in cancer cells. Methods in Enzymology, 382, 320-51.
Buranrat, B., Chau-in, S., Prawan, A., Puapairoj, A., Zeekpudsa, P. & Kukongviriyapan, V. (2012). NQO1 expression correlates with cholangiocarcinoma prognosis. Asian Pacific Journal of Cancer Prevention, 13 Suppl, 131-6.
Buranrat, B., Prawan, A., Kukongviriyapan, U., Kongpetch, S. & Kukongviriyapan, V. (2010). Dicoumarol enhances gemcitabine-induced cytotoxicity in high NQO1-expressing cholangiocarcinoma cells. World Journal of Gastroenterology, 16(19), 2362-70.
Eyssen-Hernandez, R., Ladoux, A. & Frelin, C. (1996). Differential regulation of cardiac heme oxygenase-1 and vascular endothelial growth factor mRNA expressions by hemin, heavy metals, heat shock and anoxia. FEBS Letters, 382(3), 229-33.
Franklin, C.C., Backos, D.S., Mohar, I., White, C.C., Forman, H.J. & Kavanagh, T.J. (2009). Structure, function, and post-translational regulation of the catalytic and modifier subunits of glutamate cysteine ligase. Molecular Aspects of Medicine, 30(1-2), 86-98.
Godwin, A.K., Meister, A., O'Dwyer, P.J., Huang, C.S., Hamilton, T.C. & Anderson, M.E. (1992). High resistance to cisplatin in human ovarian cancer cell lines is associated with marked increase of glutathione synthesis. Proceedings of the National Academy of Sciences of the United States of America, 89(7), 3070-4.
Hadzic, T., Aykin-Burns, N., Zhu, Y., Coleman, M.C., Leick, K., Jacobson, G.M. & Spitz, D.R. (2010). Paclitaxel combined with inhibitors of glucose and hydroperoxide metabolism enhances breast cancer cell killing via H2O2-mediated oxidative stress. Free Radical Biology and Medicine, 48(8), 1024-33.
Heasman, S.A., Zaitseva, L., Bowles, K.M., Rushworth, S.A. & Macewan, D.J. (2011). Protection of acute myeloid leukaemia cells from apoptosis induced by front-line chemotherapeutics is mediated by haem oxygenase-1. Oncotarget, 2(9), 658-68.
Hernandez-Breijo, B., Monserrat, J., Ramirez-Rubio, S., Cuevas, E.P., Vara, D., Diaz-Laviada, I., Fernandez-Moreno, M.D., Roman, I.D., Gisbert, J.P. & Guijarro, L.G. (2011). Preclinical evaluation of azathioprine plus buthionine sulfoximine in the treatment of human hepatocarcinoma and colon carcinoma. World Journal of Gastroenterology, 17(34), 3899-911.
Hirai, K., Sasahira, T., Ohmori, H., Fujii, K. & Kuniyasu, H. (2006). Inhibition of heme oxygenase-1 by zinc protoporphyrin IX reduces tumor growth of LL/2 lung cancer in C57BL mice. International Journal of Cancer, 120(3), 500–505.
Jozkowicz, A., Was, H. & Dulak, J. (2007). Heme oxygenase-1 in tumors: is it a false friend? Antioxidants & Redox Signaling, 9(12), 2099-117.
Kigawa, J., Minagawa, Y., Cheng, X. & Terakawa, N. (1998). Gamma-glutamyl cysteine synthetase up-regulates glutathione and multidrug resistance-associated protein in patients with chemoresistant epithelial ovarian cancer. Clinical Cancer Research, 4(7), 1737-41.
Kongpetch, S., Kukongviriyapan, V., Prawan, A., Senggunprai, L., Kukongviriyapan, U. & Buranrat, B. (2012). Crucial role of heme oxygenase-1 on the sensitivity of cholangiocarcinoma cells to chemotherapeutic agents. PLoS One, 7(4), e34994.
Kongpetch, S., Puapairoj, A., Ong, C.K., Senggunprai, L., Prawan, A., Kukongviriyapan, U., Chan-On, W., Siew, E.Y., Khuntikeo, N., Teh, B.T. & Kukongviriyapan, V. (2016). Haem oxygenase 1 expression is associated with prognosis in cholangiocarcinoma patients and with drug sensitivity in xenografted mice. Cell Proliferation, 49(1), 90-101.
Kuroda, H., Takeno, M., Murakami, S., Miyazawa, N., Kaneko, T. & Ishigatsubo, Y. (2010). Inhibition of heme oxygenase-1 with an epidermal growth factor receptor inhibitor and cisplatin decreases proliferation of lung cancer A549 cells. Lung Cancer, 67(1), 31-6.
Liu, K., Jin, B., Wu, C., Yang, J., Zhan, X., Wang, L., Shen, X., Chen, J., Chen, H. & Mao, Z. (2015). NQO1 Stabilizes p53 in Response to Oncogene-Induced Senescence. International Journal of Biological Sciences, 11(7), 762-71.
Liu, M., Zhao, Y. & Zhang, X. (2015). Knockdown of glutamate cysteine ligase catalytic subunit by siRNA causes the gold nanoparticles-induced cytotoxicity in lung cancer cells. PLoS One, 10(3), e0118870.
Lopes-Coelho, F., Gouveia-Fernandes, S., Goncalves, L.G., Nunes, C., Faustino, I., Silva, F., Felix, A., Pereira, S.A. & Serpa, J. (2016). HNF1beta drives glutathione (GSH) synthesis underlying intrinsic carboplatin resistance of ovarian clear cell carcinoma (OCCC). Tumour Biology, 37(4), 4813-29.
Lu, S.C. (2009). Regulation of glutathione synthesis. Molecular Aspects of Medicine, 30(1-2), 42-59.
Machlin, L.J. & Bendich, A. (1987). Free radical tissue damage: protective role of antioxidant nutrients. The FASEB Journal, 1(6), 441-5.
Matsui, Y., Watanabe, J., Ding, S., Nishizawa, K., Kajita, Y., Ichioka, K., Saito, R., Kobayashi, T., Ogawa, O. & Nishiyama, H. (2010). Dicoumarol enhances doxorubicin-induced cytotoxicity in p53 wild-type urothelial cancer cells through p38 activation. BJU International, 105(4), 558-64.
Miyake, M., Fujimoto, K., Anai, S., Ohnishi, S., Nakai, Y., Inoue, T., Matsumura, Y., Tomioka, A., Ikeda, T., Tanaka, N. & Hirao, Y. (2010). Clinical significance of heme oxygenase-1 expression in non-muscle-invasive bladder cancer. Urologia Internationalis, 85(3), 355-63.
Mulcahy, R.T., Untawale, S. & Gipp, J.J. (1994). Transcriptional up-regulation of gamma-glutamylcysteine synthetase gene expression in melphalan-resistant human prostate carcinoma cells. Molecular Pharmacology, 46(5), 909-14.
Ndisang, J.F. & Jadhav, A. (2009). Up-regulating the heme oxygenase system enhances insulin sensitivity and improves glucose metabolism in insulin-resistant diabetes in Goto-Kakizaki rats. Endocrinology, 150(6), 2627-36.
Ndisang, J.F., Lane, N., Syed, N. & Jadhav, A. (2010). Up-regulating the heme oxygenase system with hemin improves insulin sensitivity and glucose metabolism in adult spontaneously hypertensive rats. Endocrinology, 151(2), 549-60.
Nuhn, P., Kunzli, B.M., Hennig, R., Mitkus, T., Ramanauskas, T., Nobiling, R., Meuer, S.C., Friess, H. & Berberat, P.O. (2009). Heme oxygenase-1 and its metabolites affect pancreatic tumor growth in vivo. Molecular Cancer, 8, 37.
Oh, E.T. & Park, H.J. (2015). Implications of NQO1 in cancer therapy. BMB Reports, 48(11), 609-17.
Oliveira, P.A., Colaco, A., Chaves, R., Guedes-Pinto, H., De-La-Cruz, P.L. & Lopes, C. (2007). Chemical carcinogenesis. Anais da Academia Brasileira de Ciências, 79(4), 593-616.
Piper, P.W. & Millson, S.H. (2011). Mechanisms of Resistance to Hsp90 Inhibitor Drugs: A Complex Mosaic Emerges. Pharmaceuticals, 4(11), 1400.
Reuter, S., Gupta, S.C., Chaturvedi, M.M. & Aggarwal, B.B. (2010). Oxidative stress, inflammation, and cancer: how are they linked? Free Radical Biology and Medicine, 49(11), 1603-16.
Ryter, S.W., Alam, J. & Choi, A.M. (2006). Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications. Physiological Reviews, 86(2), 583-650.
Siegel, D., Franklin, W.A. & Ross, D. (1998). Immunohistochemical detection of NAD(P)H:quinone oxidoreductase in human lung and lung tumors. Clinical Cancer Research, 4(9), 2065-70.
Sullivan, L.B. & Chandel, N.S. (2014). Mitochondrial reactive oxygen species and cancer. Cancer & Metabolism, 2, 17.
Toroser, D. & Sohal, R.S. (2007). Age-associated perturbations in glutathione synthesis in mouse liver. Biochemical Journal, 405(3), 583-9.
Trachootham, D., Alexandre, J. & Huang, P. (2009). Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nature Reviews Drug Discovery, 8(7), 579-91.
Tsai, J.R., Wang, H.M., Liu, P.L., Chen, Y.H., Yang, M.C., Chou, S.H., Cheng, Y.J., Yin, W.H., Hwang, J.J. & Chong, I.W. (2012). High expression of heme oxygenase-1 is associated with tumor invasiveness and poor clinical outcome in non-small cell lung cancer patients. Cellular Oncology, 35(6), 461-71.
Volpato, M. & Phillips, R.M. (2007). Tailoring targeted therapy to individual patients: lessons to be learnt from the development of mitomycin C. Cancer Genomics Proteomics, 4(3), 175-86.
Willcox, J.K., Ash, S.L. & Catignani, G.L. (2004). Antioxidants and prevention of chronic disease. Critical Reviews in Food Science and Nutrition, 44(4), 275-95.
Yachie, A., Niida, Y., Wada, T., Igarashi, N., Kaneda, H., Toma, T., Ohta, K., Kasahara, Y. & Koizumi, S. (1999). Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. The Journal of Clinical Investigation, 103(1), 129-35.
Yin, Y., Liu, Q., Wang, B., Chen, G., Xu, L. & Zhou, H. (2012). Expression and function of heme oxygenase-1 in human gastric cancer. Experimental Biology and Medicine, 237(4), 362-71.
Zeekpudsa, P., Kukongviriyapan, V., Senggunprai, L., Sripa, B. & Prawan, A. (2014). Suppression of NAD(P)H-quinone oxidoreductase 1 enhanced the susceptibility of cholangiocarcinoma cells to chemotherapeutic agents. Journal of Experimental & Clinical Cancer Research, 33, 11.
Zimmerman, R. & Cerutti, P. (1984). Active oxygen acts as a promoter of transformation in mouse embryo C3H/10T1/2/C18 fibroblasts. Proceedings of the National Academy of Sciences of the United States of America, 81(7), 2085-7.
Ames, B.N., Shigenaga, M.K. & Hagen, T.M. (1993). Oxidants, antioxidants, and the degenerative diseases of aging. Proceedings of the National Academy of Sciences of the United States of America, 90(17), 7915-22.
Awadallah, N.S., Dehn, D., Shah, R.J., Russell Nash, S., Chen, Y.K., Ross, D., Bentz, J.S. & Shroyer, K.R. (2008). NQO1 expression in pancreatic cancer and its potential use as a biomarker. Applied Immunohistochemistry & Molecular Morphology, 16(1), 24-31.
Begleiter, A. & Fourie, J. (2004). Induction of NQO1 in cancer cells. Methods in Enzymology, 382, 320-51.
Buranrat, B., Chau-in, S., Prawan, A., Puapairoj, A., Zeekpudsa, P. & Kukongviriyapan, V. (2012). NQO1 expression correlates with cholangiocarcinoma prognosis. Asian Pacific Journal of Cancer Prevention, 13 Suppl, 131-6.
Buranrat, B., Prawan, A., Kukongviriyapan, U., Kongpetch, S. & Kukongviriyapan, V. (2010). Dicoumarol enhances gemcitabine-induced cytotoxicity in high NQO1-expressing cholangiocarcinoma cells. World Journal of Gastroenterology, 16(19), 2362-70.
Eyssen-Hernandez, R., Ladoux, A. & Frelin, C. (1996). Differential regulation of cardiac heme oxygenase-1 and vascular endothelial growth factor mRNA expressions by hemin, heavy metals, heat shock and anoxia. FEBS Letters, 382(3), 229-33.
Franklin, C.C., Backos, D.S., Mohar, I., White, C.C., Forman, H.J. & Kavanagh, T.J. (2009). Structure, function, and post-translational regulation of the catalytic and modifier subunits of glutamate cysteine ligase. Molecular Aspects of Medicine, 30(1-2), 86-98.
Godwin, A.K., Meister, A., O'Dwyer, P.J., Huang, C.S., Hamilton, T.C. & Anderson, M.E. (1992). High resistance to cisplatin in human ovarian cancer cell lines is associated with marked increase of glutathione synthesis. Proceedings of the National Academy of Sciences of the United States of America, 89(7), 3070-4.
Hadzic, T., Aykin-Burns, N., Zhu, Y., Coleman, M.C., Leick, K., Jacobson, G.M. & Spitz, D.R. (2010). Paclitaxel combined with inhibitors of glucose and hydroperoxide metabolism enhances breast cancer cell killing via H2O2-mediated oxidative stress. Free Radical Biology and Medicine, 48(8), 1024-33.
Heasman, S.A., Zaitseva, L., Bowles, K.M., Rushworth, S.A. & Macewan, D.J. (2011). Protection of acute myeloid leukaemia cells from apoptosis induced by front-line chemotherapeutics is mediated by haem oxygenase-1. Oncotarget, 2(9), 658-68.
Hernandez-Breijo, B., Monserrat, J., Ramirez-Rubio, S., Cuevas, E.P., Vara, D., Diaz-Laviada, I., Fernandez-Moreno, M.D., Roman, I.D., Gisbert, J.P. & Guijarro, L.G. (2011). Preclinical evaluation of azathioprine plus buthionine sulfoximine in the treatment of human hepatocarcinoma and colon carcinoma. World Journal of Gastroenterology, 17(34), 3899-911.
Hirai, K., Sasahira, T., Ohmori, H., Fujii, K. & Kuniyasu, H. (2006). Inhibition of heme oxygenase-1 by zinc protoporphyrin IX reduces tumor growth of LL/2 lung cancer in C57BL mice. International Journal of Cancer, 120(3), 500–505.
Jozkowicz, A., Was, H. & Dulak, J. (2007). Heme oxygenase-1 in tumors: is it a false friend? Antioxidants & Redox Signaling, 9(12), 2099-117.
Kigawa, J., Minagawa, Y., Cheng, X. & Terakawa, N. (1998). Gamma-glutamyl cysteine synthetase up-regulates glutathione and multidrug resistance-associated protein in patients with chemoresistant epithelial ovarian cancer. Clinical Cancer Research, 4(7), 1737-41.
Kongpetch, S., Kukongviriyapan, V., Prawan, A., Senggunprai, L., Kukongviriyapan, U. & Buranrat, B. (2012). Crucial role of heme oxygenase-1 on the sensitivity of cholangiocarcinoma cells to chemotherapeutic agents. PLoS One, 7(4), e34994.
Kongpetch, S., Puapairoj, A., Ong, C.K., Senggunprai, L., Prawan, A., Kukongviriyapan, U., Chan-On, W., Siew, E.Y., Khuntikeo, N., Teh, B.T. & Kukongviriyapan, V. (2016). Haem oxygenase 1 expression is associated with prognosis in cholangiocarcinoma patients and with drug sensitivity in xenografted mice. Cell Proliferation, 49(1), 90-101.
Kuroda, H., Takeno, M., Murakami, S., Miyazawa, N., Kaneko, T. & Ishigatsubo, Y. (2010). Inhibition of heme oxygenase-1 with an epidermal growth factor receptor inhibitor and cisplatin decreases proliferation of lung cancer A549 cells. Lung Cancer, 67(1), 31-6.
Liu, K., Jin, B., Wu, C., Yang, J., Zhan, X., Wang, L., Shen, X., Chen, J., Chen, H. & Mao, Z. (2015). NQO1 Stabilizes p53 in Response to Oncogene-Induced Senescence. International Journal of Biological Sciences, 11(7), 762-71.
Liu, M., Zhao, Y. & Zhang, X. (2015). Knockdown of glutamate cysteine ligase catalytic subunit by siRNA causes the gold nanoparticles-induced cytotoxicity in lung cancer cells. PLoS One, 10(3), e0118870.
Lopes-Coelho, F., Gouveia-Fernandes, S., Goncalves, L.G., Nunes, C., Faustino, I., Silva, F., Felix, A., Pereira, S.A. & Serpa, J. (2016). HNF1beta drives glutathione (GSH) synthesis underlying intrinsic carboplatin resistance of ovarian clear cell carcinoma (OCCC). Tumour Biology, 37(4), 4813-29.
Lu, S.C. (2009). Regulation of glutathione synthesis. Molecular Aspects of Medicine, 30(1-2), 42-59.
Machlin, L.J. & Bendich, A. (1987). Free radical tissue damage: protective role of antioxidant nutrients. The FASEB Journal, 1(6), 441-5.
Matsui, Y., Watanabe, J., Ding, S., Nishizawa, K., Kajita, Y., Ichioka, K., Saito, R., Kobayashi, T., Ogawa, O. & Nishiyama, H. (2010). Dicoumarol enhances doxorubicin-induced cytotoxicity in p53 wild-type urothelial cancer cells through p38 activation. BJU International, 105(4), 558-64.
Miyake, M., Fujimoto, K., Anai, S., Ohnishi, S., Nakai, Y., Inoue, T., Matsumura, Y., Tomioka, A., Ikeda, T., Tanaka, N. & Hirao, Y. (2010). Clinical significance of heme oxygenase-1 expression in non-muscle-invasive bladder cancer. Urologia Internationalis, 85(3), 355-63.
Mulcahy, R.T., Untawale, S. & Gipp, J.J. (1994). Transcriptional up-regulation of gamma-glutamylcysteine synthetase gene expression in melphalan-resistant human prostate carcinoma cells. Molecular Pharmacology, 46(5), 909-14.
Ndisang, J.F. & Jadhav, A. (2009). Up-regulating the heme oxygenase system enhances insulin sensitivity and improves glucose metabolism in insulin-resistant diabetes in Goto-Kakizaki rats. Endocrinology, 150(6), 2627-36.
Ndisang, J.F., Lane, N., Syed, N. & Jadhav, A. (2010). Up-regulating the heme oxygenase system with hemin improves insulin sensitivity and glucose metabolism in adult spontaneously hypertensive rats. Endocrinology, 151(2), 549-60.
Nuhn, P., Kunzli, B.M., Hennig, R., Mitkus, T., Ramanauskas, T., Nobiling, R., Meuer, S.C., Friess, H. & Berberat, P.O. (2009). Heme oxygenase-1 and its metabolites affect pancreatic tumor growth in vivo. Molecular Cancer, 8, 37.
Oh, E.T. & Park, H.J. (2015). Implications of NQO1 in cancer therapy. BMB Reports, 48(11), 609-17.
Oliveira, P.A., Colaco, A., Chaves, R., Guedes-Pinto, H., De-La-Cruz, P.L. & Lopes, C. (2007). Chemical carcinogenesis. Anais da Academia Brasileira de Ciências, 79(4), 593-616.
Piper, P.W. & Millson, S.H. (2011). Mechanisms of Resistance to Hsp90 Inhibitor Drugs: A Complex Mosaic Emerges. Pharmaceuticals, 4(11), 1400.
Reuter, S., Gupta, S.C., Chaturvedi, M.M. & Aggarwal, B.B. (2010). Oxidative stress, inflammation, and cancer: how are they linked? Free Radical Biology and Medicine, 49(11), 1603-16.
Ryter, S.W., Alam, J. & Choi, A.M. (2006). Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications. Physiological Reviews, 86(2), 583-650.
Siegel, D., Franklin, W.A. & Ross, D. (1998). Immunohistochemical detection of NAD(P)H:quinone oxidoreductase in human lung and lung tumors. Clinical Cancer Research, 4(9), 2065-70.
Sullivan, L.B. & Chandel, N.S. (2014). Mitochondrial reactive oxygen species and cancer. Cancer & Metabolism, 2, 17.
Toroser, D. & Sohal, R.S. (2007). Age-associated perturbations in glutathione synthesis in mouse liver. Biochemical Journal, 405(3), 583-9.
Trachootham, D., Alexandre, J. & Huang, P. (2009). Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nature Reviews Drug Discovery, 8(7), 579-91.
Tsai, J.R., Wang, H.M., Liu, P.L., Chen, Y.H., Yang, M.C., Chou, S.H., Cheng, Y.J., Yin, W.H., Hwang, J.J. & Chong, I.W. (2012). High expression of heme oxygenase-1 is associated with tumor invasiveness and poor clinical outcome in non-small cell lung cancer patients. Cellular Oncology, 35(6), 461-71.
Volpato, M. & Phillips, R.M. (2007). Tailoring targeted therapy to individual patients: lessons to be learnt from the development of mitomycin C. Cancer Genomics Proteomics, 4(3), 175-86.
Willcox, J.K., Ash, S.L. & Catignani, G.L. (2004). Antioxidants and prevention of chronic disease. Critical Reviews in Food Science and Nutrition, 44(4), 275-95.
Yachie, A., Niida, Y., Wada, T., Igarashi, N., Kaneda, H., Toma, T., Ohta, K., Kasahara, Y. & Koizumi, S. (1999). Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. The Journal of Clinical Investigation, 103(1), 129-35.
Yin, Y., Liu, Q., Wang, B., Chen, G., Xu, L. & Zhou, H. (2012). Expression and function of heme oxygenase-1 in human gastric cancer. Experimental Biology and Medicine, 237(4), 362-71.
Zeekpudsa, P., Kukongviriyapan, V., Senggunprai, L., Sripa, B. & Prawan, A. (2014). Suppression of NAD(P)H-quinone oxidoreductase 1 enhanced the susceptibility of cholangiocarcinoma cells to chemotherapeutic agents. Journal of Experimental & Clinical Cancer Research, 33, 11.
Zimmerman, R. & Cerutti, P. (1984). Active oxygen acts as a promoter of transformation in mouse embryo C3H/10T1/2/C18 fibroblasts. Proceedings of the National Academy of Sciences of the United States of America, 81(7), 2085-7.
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2016-08-11
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