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Double-Sided Personality: Effects of Arsenic Trioxide on Inflammation

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Abstract

In 1992, arsenic trioxide (As2O3, ATO) was demonstrated to be an effective therapeutic agent against acute promyelocytic leukemia (APL), rekindling attention to ATO applications in U.S. Food and Drug Administration clinical trials for the treatment of cancers, such as leukemia, lymphomas, and solid tumors. ATO is a potent chemotherapeutic drug that can also be used to treat other diseases, such as autoimmune diseases, because it affects multiple pathways including apoptosis induction, differentiation stimulation, and proliferation inhibition. As inflammation is a critical component of disease progression, ATO is a feasible treatment option based on its ability to protect against inflammation. However, ATO is also a well-known carcinogen because of its pro-inflammatory effect. This review will focus on the double-sided effects of ATO on inflammation as well as the relevant mechanisms underlying these effects, aiming to provide a rational understanding of how ATO effects the immune system. We especially aim to provide a comprehensive overview of our current knowledge of how ATO influences inflammation.

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References

  1. Sun, H., L. Ma, Z. Hu, et al. 1992. Arsenic trioxide treated 32 cases of acute promyelocytic leukemia. Chinese Journal of Integrated Traditional and Western Medicine 12: 170–172.

    Google Scholar 

  2. Oketani, M., K. Kohara, D. Tuvdendorj, K. Ishitsuka, Y. Komorizono, K. Ishibashi, and T. Arima. 2002. Inhibition by arsenic trioxide of human hepatoma cell growth. Cancer Letter 183: 147–153.

    Article  CAS  Google Scholar 

  3. Li, X., X. Ding, and T.E. Adrian. 2002. Arsenic trioxide inhibits proliferation and induces apoptosis in pancreatic cancer cells. Anticancer Research 22: 2205–2213.

    PubMed  CAS  Google Scholar 

  4. Zhang, J., C. Li, Y. Zheng, Z. Lin, Y. Zhang, and Z. Zhang. 2017. Inhibition of angiogenesis by arsenic trioxide via TSP-1-TGF-beta1-CTGF-VEGF functional module in rheumatoid arthritis. Oncotarget 8: 73529–73546. https://doi.org/10.18632/oncotarget.19867.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Coussens, L.M., and Z. Werb. 2002. Inflammation and cancer. Nature 420: 860–867.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Shen, L., F. Gong, W. Tian, W. Li, F. Zhang, J. Qian, A. Sun, Y. Zou, W. Yang, and J. Ge. 2013. Anti-inflammatory effects of arsenic trioxide eluting stents in a porcine coronary model. BioMed Research International 2013 (937936): 1–9. https://doi.org/10.1155/2013/937936.

    Article  CAS  Google Scholar 

  7. Raman, M., W. Chen, and M.H. Cobb. 2007. Differential regulation and properties of MAPKs. Oncogene 26: 3100–3112.

    Article  PubMed  CAS  Google Scholar 

  8. Cavigelli, M., W.W. Li, A. Lin, B. Su, K. Yoshioka, and M. Karin. 1996. The tumor promoter arsenite stimulates AP-1 activity by inhibiting a JNK phosphatase. EMBO Journal 15: 6269–6279.

    Article  PubMed  CAS  Google Scholar 

  9. Kajiguchi, T., K. Yamamoto, S. Iida, R. Ueda, N. Emi, and T. Naoe. 2006. Sustained activation of c-jun-N-terminal kinase plays a critical role in arsenic trioxide-induced cell apoptosis in multiple myeloma cell lines. Cancer Science 97: 540–545.

    Article  PubMed  CAS  Google Scholar 

  10. Wu, W., L.M. Graves, I. Jaspers, et al. 1999. Activation of the EGF receptor signaling pathway in human airway epithelial cells exposed to metals. American Journal Physiology 277: L924–L931.

    CAS  Google Scholar 

  11. Shim, M.J., H.J. Kim, S.J. Yang, et al. 2002. Arsenic trioxide induces apoptosis in chronic myelogenous leukemia K562 cells: possible involvement of p38 MAP kinase. Journal Biochemical Molecular Biological 35: 377–383.

    CAS  Google Scholar 

  12. Binet, F., H. Cavalli, E. Moisan, et al. 2006. Arsenic trioxide (AT) is a novel human neutrophil pro-apoptotic agent: effects of catalase on AT-induced apoptosis, degradation of cytoskeletal proteins and de novo protein synthesis. Haematology 132: 349–358.

    CAS  Google Scholar 

  13. Singer, M., G. Trugnan, and M.K. Chelbi-Alix. 2011. Arsenic trioxide reduces 2,4,6-trinitrobenzene sulfonic acid-induced murine colitis via nuclear factor-kappaB down-regulation and caspase-3 activation. Innate Immunology 17: 365–374.

    Article  CAS  Google Scholar 

  14. Binet, F., S. Chiasson, and D. Girard. 2010. Evidence that endoplasmic reticulum (ER) stress and caspase-4 activation occur in human neutrophils. Biochemical Biophysical Research Communications 391: 18–23.

    Article  PubMed  CAS  Google Scholar 

  15. Gupta, S., L. Yel, D. Kim, et al. 2003. Arsenic trioxide induces apoptosis in peripheral blood T lymphocyte subsets by inducing oxidative stress: a role of Bcl-2. Molecular Cancer Therapy 2: 711–719.

    Article  CAS  Google Scholar 

  16. Bobe, P., D. Bonardelle, K. Benihoud, P. Opolon, and M.K. Chelbi-Alix. 2006. Arsenic trioxide: a promising novel therapeutic agent for lymphoproliferative and autoimmune syndromes in MRL/lpr mice. Blood 108: 3967–3975.

    Article  PubMed  CAS  Google Scholar 

  17. Li, K., L. Zhang, X. Xiang, et al. 2013. Arsenic trioxide alleviates airway hyperresponsiveness and promotes apoptosis of CD4+ T lymphocytes: evidence for involvement of the ER stress-CHOP pathway. Journal Medical Science 182: 573–583.

    CAS  Google Scholar 

  18. Zhou, L.F., and K.S. Yin. 2002. Effect of arsenic trioxide on apoptosis of pulmonary eosinophile in asthmatic guinea-pigs. Zhongguo Zhong Xi Yi Jie He Za Zhi 22: 292–294.

    PubMed  Google Scholar 

  19. Zhang, L., K. Li, L. Bing Ma, et al. 2012. Effects and mechanism of arsenic trioxide on reversing the asthma pathologies including Th17-IL-17 axis in a mouse model. Iran Journal Allergy Asthma Immunology 11: 133–145.

    CAS  Google Scholar 

  20. Lemarie, A., C. Morzadec, D. Merino, et al. 2006. Arsenic trioxide induces apoptosis of human monocytes during macrophagic differentiation through nuclear factor-kappaB-related survival pathway down-regulation. Journal Pharmacological Experimetal Therapy 316: 304–314.

    Article  CAS  Google Scholar 

  21. Rousselot, P., S. Labaume, J.P. Marolleau, et al. 1999. Arsenic trioxide and melarsoprol induce apoptosis in plasma cell lines and in plasma cells from myeloma patients. Cancer Research 59: 1041–1048.

    PubMed  CAS  Google Scholar 

  22. Xue, D.B., W.H. Zhang, X.G. Yun, et al. 2007. Regulating effects of arsenic trioxide on cell death pathways and inflammatory reactions of pancreatic acinar cells in rats. Chinical Medical Journal 120: 690–695.

    CAS  Google Scholar 

  23. Burchiel, S.W., L.A. Mitchell, F.T. Lauer, X. Sun, J.D. McDonald, L.G. Hudson, and K.J. Liu. 2009. Immunotoxicity and biodistribution analysis of arsenic trioxide in C57Bl/6 mice following a 2-week inhalation exposure. Toxicol Pharmacology 241: 253–259.

    Article  CAS  Google Scholar 

  24. Tohyama, N., S. Tanaka, K. Onda, K. Sugiyama, and T. Hirano. 2013. Influence of anticancer agents on cell survival, proliferation, and CD4+CD25+Foxp3+ regulatory T cell-frequency in human peripheral-blood mononuclear cells activated by T cell-mitogen. International Immunopharmacology 15: 160–166.

    Article  PubMed  CAS  Google Scholar 

  25. Takahashi, M., A. Ota, S. Karnan, E. Hossain, Y. Konishi, L. Damdindorj, H. Konishi, T. Yokochi, M. Nitta, and Y. Hosokawa. 2013. Arsenic trioxide prevents nitric oxide production in lipopolysaccharide -stimulated RAW 264.7 by inhibiting a TRIF-dependent pathway. Cancer Science 104: 165–170.

    Article  PubMed  CAS  Google Scholar 

  26. Lemarie, A., E. Bourdonnay, C. Morzadec, O. Fardel, and L. Vernhet. 2008. Inorganic arsenic activates reduced NADPH oxidase in human primary macrophages through a Rho kinase/p38 kinase pathway. Journal Immunology 180: 6010–6017.

    Article  CAS  Google Scholar 

  27. Srivastava, R.K., C. Li, S.C. Chaudhary, M.E. Ballestas, C.A. Elmets, D.J. Robbins, S. Matalon, J.S. Deshane, F. Afaq, D.R. Bickers, and M. Athar. 2013. Unfolded protein response (UPR) signaling regulates arsenic trioxide-mediated macrophage innate immune function disruption. Toxicol Pharmacology 272: 879–887.

    Article  CAS  Google Scholar 

  28. Maier, N.K., D. Crown, J. Liu, S.H. Leppla, and M. Moayeri. 2014. Arsenic trioxide and other arsenical compounds inhibit the NLRP1, NLRP3, and NAIP5/NLRC4 inflammasomes. Journal Immunology 192: 763–770.

    Article  CAS  Google Scholar 

  29. Binet, F., S. Chiasson, and D. Girard. 2008. Arsenic trioxide induces de novo protein synthesis of annexin-1 in neutrophils: association with a heat shock-like response and not apoptosis. British Journal Haematology 140: 454–463.

    Article  CAS  Google Scholar 

  30. Chu, K.H., C.C. Lee, S.C. Hsin, B.C. Cai, J.H. Wang, and B.L. Chiang. 2010. Arsenic trioxide alleviates airway hyperresponsiveness and eosinophilia in a murine model of asthma. Cell Molecular Immunology 7: 375–380.

    Article  CAS  Google Scholar 

  31. Zhou, L.F., Y. Zhu, X.F. Cui, W.P. Xie, A.H. Hu, and K.S. Yin. 2006. Arsenic trioxide, a potent inhibitor of NF-kappaB, abrogates allergen-induced airway hyperresponsiveness and inflammation. Respiration Research 7: 146.

    Article  CAS  Google Scholar 

  32. Mei, Y., Y. Zheng, H. Wang, et al. 2011. Arsenic trioxide induces apoptosis of fibroblast-like synoviocytes and represents antiarthritis effect in experimental model of rheumatoid arthritis. Journal of Rheumatology 38: 36–43.

    Article  PubMed  CAS  Google Scholar 

  33. Zhang, K., P. Zhao, G. Guo, Y. Guo, L. Tian, X. Sun, S. Li, Y. He, Y. Sun, H. Chai, W. Zhang, and M. Xing. 2016. Arsenic trioxide attenuates NF-kappaB and cytokine mRNA levels in the livers of cocks. Biological Trace Research 170: 432–437.

    Article  CAS  Google Scholar 

  34. Li, S.W., X. Sun, Y. He, Y. Guo, H.J. Zhao, Z.J. Hou, and M.W. Xing. 2017. Assessment of arsenic trioxide in the heart of Gallus gallus: alterations of oxidative damage parameters, inflammatory cytokines, and cardiac enzymes. Environmental Science of Pollut Researcg International 24: 5781–5790.

    Article  CAS  Google Scholar 

  35. Xing, M., P. Zhao, G. Guo, Y. Guo, K. Zhang, L. Tian, Y. He, H. Chai, and W. Zhang. 2015. Inflammatory factor alterations in the gastrointestinal tract of cocks overexposed to arsenic trioxide. Biological Trace Research 167: 288–299.

    Article  CAS  Google Scholar 

  36. Binet, F., and D. Girard. 2008. Novel human neutrophil agonistic properties of arsenic trioxide: involvement of p38 mitogen-activated protein kinase and/or c-jun NH2-terminal MAPK but not extracellular signal-regulated kinases-1/2. Journal Leukocytic Biological 84: 1613–1622.

    Article  CAS  Google Scholar 

  37. Bourdonnay, E., C. Morzadec, O. Fardel, and L. Vernhet. 2011. Arsenic increases lipopolysaccharide-dependent expression of interleukin-8 gene by stimulating a redox-sensitive pathway that strengthens p38-kinase activation. Molecular Immunology 48: 2069–2078.

    Article  PubMed  CAS  Google Scholar 

  38. Chen, G., J. Mao, J. Zhao, Y. Zhang, T. Li, C. Wang, L. Xu, Q. Hu, X. Wang, S. Jiang, X. Nie, and Q. Wu. 2016. Arsenic trioxide mediates HAPI microglia inflammatory response and the secretion of inflammatory cytokine IL-6 via Akt/NF-kappaB signaling pathway. Regulation of Toxicol Pharmacology 81: 480–488.

    Article  CAS  Google Scholar 

  39. Mao, J., J. Yang, Y. Zhang, T. Li, C. Wang, L. Xu, Q. Hu, X. Wang, S. Jiang, X. Nie, and G. Chen. 2016. Arsenic trioxide mediates HAPI microglia inflammatory response and subsequent neuron apoptosis through p38/JNK MAPK/STAT3 pathway. Toxicol Application Pharmacology 303: 79–89.

    Article  CAS  Google Scholar 

  40. Wang, Q., L. Wu, and J. Wang. 2013. Reciprocal regulation of cyclooxygenase 2 and heme oxygenase 1 upon arsenic trioxide exposure in normal human lung fibroblast. Journal Biochemical Molecular Toxicology 27: 323–329.

    Article  CAS  Google Scholar 

  41. Ma, Y., Z. Ma, S. Yin, X. Yan, and J. Wang. 2017. Arsenic and fluoride induce apoptosis, inflammation and oxidative stress in cultured human umbilical vein endothelial cells. Chemosphere 167: 454–461.

    Article  PubMed  CAS  Google Scholar 

  42. Udensi, U.K., H.H. Cohly, B.E. Graham-Evans, K. Ndebele, N. Garcia-Reyero, B. Nanduri, P.B. Tchounwou, and R.D. Isokpehi. 2011. Aberrantly expressed genes in HaCaT keratinocytes chronically exposed to arsenic trioxide. Biomarker Insights 6: 7–16.

    PubMed  PubMed Central  CAS  Google Scholar 

  43. Saint-Jacques, N., L. Parker, P. Brown, and T.J.B. Dummer. 2014. Arsenic in drinking water and urinary tract cancers: a systematic review of 30 years of epidemiological evidence. Environmental Health 13: 44.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Antonelli, R., K. Shao, D.J. Thomas, R. Sams II, and J. Cowden. 2014. AS3MT, GSTO, and PNP polymorphisms: impact on arsenic methylation and implications for disease susceptibility. Environmetal Research 132: 156–167.

    Article  CAS  Google Scholar 

  45. Hirano, S., Y. Kobayashi, X. Cui, S. Kanno, T. Hayakawa, and A. Shraim. 2004. The accumulation and toxicity of methylated arsenicals in endothelial cells: important roles of thiol compounds. Toxicol Application Pharmacology 198: 458–467.

    Article  CAS  Google Scholar 

  46. Huang, C., W.Y. Ma, J. Li, A. Goranson, and Z. Dong. 1999. Requirement of Erk, but not JNK, for arsenite-induced cell transformation. Journal Biological Chemistry 274: 14595–14601.

    Article  CAS  Google Scholar 

  47. Chen, G.Q., L. Zhou, M. Styblo, F. Walton, Y. Jing, R. Weinberg, Z. Chen, and S. Waxman. 2003. Methylated metabolites of arsenic trioxide are more potent than arsenic trioxide as apoptotic but not differentiation inducers in leukemia and lymphoma cells. Cancer Research 63: 1853–1859.

    PubMed  CAS  Google Scholar 

  48. Xu, S., Y.F. Zhang, M.W. Carew, W.H. Hao, J.F.C. Loo, H. Naranmandura, and X. Chris le. 2013. Multidrug resistance protein 1 (ABCC1) confers resistance to arsenic compounds in human myeloid leukemic HL-60 cells. Archives of Toxicology 87: 1013–1023.

    Article  PubMed  CAS  Google Scholar 

  49. Xu, W.X., Y. Liu, S.Z. Liu, Y. Zhang, G.F. Qiao, and J. Yan. 2014. Arsenic trioxide exerts a double effect on osteoblast growth in vitro. Environental Toxicology Pharmacology 38: 412–419.

    Article  CAS  Google Scholar 

  50. Chen, G.Q., X.G. Shi, W. Tang, S.M. Xiong, J. Zhu, X. Cai, Z.G. Han, J.H. Ni, G.Y. Shi, P.M. Jia, M.M. Liu, K.L. He, C. Niu, J. Ma, P. Zhang, T.D. Zhang, P. Paul, T. Naoe, K. Kitamura, W. Miller, S. Waxman, Z.Y. Wang, H. de The, S.J. Chen, and Z. Chen. 1997. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): I. As2O3 exerts dose-dependent dual effects on APL cells. Blood 89: 3345–3353.

    PubMed  CAS  Google Scholar 

  51. Martin-Chouly, C., C. Morzadec, M. Bonvalet, M.D. Galibert, O. Fardel, and L. Vernhet. 2011. Inorganic arsenic alters expression of immune and stress response genes in activated primary human T lymphocytes. Molecular Immunology 48: 956–965.

    Article  PubMed  CAS  Google Scholar 

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This work is supported by the National Natural Science Foundation of China (NSFC 81771749) to Zhiyi Zhang.

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Zhang, J., Zhang, Y., Wang, W. et al. Double-Sided Personality: Effects of Arsenic Trioxide on Inflammation. Inflammation 41, 1128–1134 (2018). https://doi.org/10.1007/s10753-018-0775-x

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