Abstract
Arsenic is one of the most abundant metals in the Earth’s crust. It exists in both organic and inorganic forms. Contamination of drinking water globally by significant environmental exposure of Arsenic is one of the major public health problems. It is found that more than 100 million people are exposed to Arsenic worldwide. Drinking water Arsenic concentration has been reported very high in many countries around the world, leading to Arsenic poisoning in the human population. International Agency of Research on Cancer (IARC) has classified Arsenic as a class I human carcinogen. There are several types of cancers associated with Arsenic toxicity, such as skin, bladder, kidney, prostate, liver and lungs cancer. Among them, skin cancer is the most common neoplasm associated with Arsenic, and lung cancer is the most deadly. Arsenic concentration in high doses has been found out in various places around the world. Though Arsenic-induced cancer is well studied, several mechanisms of the same are unknown. Here, we have investigated the mechanism of carcinogenesis induced by inorganic Arsenic and its role in oxidative stress, apoptosis, Arsenic-induced DNA damage, role in affecting signal transduction pathways, epigenetic modifications due to Arsenic, genotoxicity caused by Arsenic, and also the role of Arsenic affecting Micro RNA. We also discussed in detail in this chapter the molecular mechanism involved in Arsenic-induced cancers such as skin, lungs, liver, prostrate, kidney and bladder. A better understanding of molecular mechanisms of Arsenic induced cancer will help us to develop effective therapeutic approach for Arsenic induced cancer.
Keywords
- Arsenic toxicity
- Cancer
- Oxidative stress
- DNA damage
- Apoptosis
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Ajees AA, Rosen BP. As(III) S-adenosylmethionine methyltransferases and other Arsenic binding proteins. Geomicrobiol J. 2015;32:570–6. https://doi.org/10.1080/01490451.2014.908983.
Arsenic species cause release of iron from ferritin generating activated oxygen. Free Radic Biol Med. 1999; https://doi.org/10.1016/s0891-5849(99)90549-x.
Arsenic trioxide-induced apoptosis in U937 cells involve generation of reactive oxygen species and inhibition of Akt – PubMed [WWW Document]; n.d.
Benbrahim-Tallaa L, Waalkes MP. Inorganic Arsenic and human prostate cancer. Environ Health Perspect. 2008;116:158–64. https://doi.org/10.1289/ehp.10423.
Benbrahim-Tallaa L, Webber MM, Waalkes MP. Mechanisms of acquired androgen independence during Arsenic-induced malignant transformation of human prostate epithelial cells. Environ Health Perspect. 2007;115:243–7. https://doi.org/10.1289/ehp.9630.
Bode AM, Dong Z. The paradox of Arsenic: molecular mechanisms of cell transformation and chemotherapeutic effects. Crit Rev Oncol Hematol. 2002; https://doi.org/10.1016/S1040-8428(01)00215-3.
Buscaglia LEB, Li Y. Apoptosis and the target genes of microRNA-21. Chin J Cancer. 2011;30:371–80. https://doi.org/10.5732/cjc.30.0371.
Bustos MA, Ono S, Marzese DM, Oyama T, Iida Y, Cheung G, Nelson N, Hsu SC, Yu Q, Hoon DSB. MiR-200a regulates CDK4/6 inhibitor effect by targeting CDK6 in metastatic melanoma. J Invest Dermatol. 2017;137:1955–64. https://doi.org/10.1016/j.jid.2017.03.039.
Cardoso APF, Al-Eryani L, Christopher States J. Arsenic-induced carcinogenesis: the impact of miRNA dysregulation. Toxicol Sci. 2018;165:284–90. https://doi.org/10.1093/toxsci/kfy128.
Chen F, Shi X. Signaling from toxic metals to NF-κB and beyond: not just a matter of reactive oxygen species. Environ Health Perspect. 2002; https://doi.org/10.1289/ehp.02110s5807.
Chen W, Martindale JL, Holbrook NJ, Liu Y. Tumor promoter Arsenite activates extracellular signal-regulated kinase through a signaling pathway mediated by epidermal growth factor receptor and Shc. Mol Cell Biol. 1998; https://doi.org/10.1128/mcb.18.9.5178.
Chen F, Vallyathan V, Castranova V, Shi X. Cell apoptosis induced by carcinogenic metals. Mol Cell Biochem. 2001;222:183–8. https://doi.org/10.1023/A:1017970330982.
Chen J-W, Chen H-Y, Li W-F, Liou S-H, Chen C-J, Wu J-H, Wang S-L. The association between total urinary Arsenic concentration and renal dysfunction in a community-based population from central Taiwan. Chemosphere. 2011;84:17–24. https://doi.org/10.1016/j.chemosphere.2011.02.091.
Chen C, Yang Q, Wang D, Luo F, Liu X, Xue J, Yang P, Xu H, Lu J, Zhang A, Liu Q. MicroRNA-191, regulated by HIF-2α, is involved in EMT and acquisition of a stem cell-like phenotype in arsenite-transformed human liver epithelial cells. Toxicol in Vitro. 2018;48:128–36. https://doi.org/10.1016/j.tiv.2017.12.016.
Chirshev E, Oberg KC, Ioffe YJ, Unternaehrer JJ. Let – 7 as biomarker, prognostic indicator, and therapy for precision medicine in cancer. Clin Transl Med. 2019;8 https://doi.org/10.1186/s40169-019-0240-y.
Chouchane S, Snow ET. In vitro effect of Arsenical compounds on glutathione-related enzymes. Chem Res Toxicol. 2001;14:517–22. https://doi.org/10.1021/tx000123x.
Cooke MS, Evans MD, Dizdaroglu M, Lunec J. Oxidative DNA damage: mechanisms, mutation, and disease. FASEB J. 2003;17:1195–214. https://doi.org/10.1096/fj.02-0752rev.
Cooper KL, Liu KJ, Hudson LG. Contributions of reactive oxygen species and mitogen-activated protein kinase signaling in arsenite-stimulated hemeoxygenase-1 production. Toxicol Appl Pharmacol. 2007; https://doi.org/10.1016/j.taap.2006.09.020.
Das S, Joardar S, Manna P, Dua TK, Bhattacharjee N, Khanra R, Bhowmick S, Kalita J, Saha A, Ray S, De Feo V, Dewanjee S. Carnosic acid, a natural diterpene, attenuates Arsenic-induced hepatotoxicity via reducing oxidative stress, MAPK activation, and apoptotic cell death pathway. Oxidative Med Cell Longev. 2018; https://doi.org/10.1155/2018/1421438.
Del Razo LM, Quintanilla-Vega B, Brambila-Colombres E, Calderón-Aranda ES, Manno M, Albores A. Stress proteins induced by Arsenic. Toxicol Appl Pharmacol. 2001;177:132–48. https://doi.org/10.1006/taap.2001.9291.
Dela Cruz CS, Tanoue LT, Matthay RA. Lung cancer: epidemiology, etiology, and prevention. Clin Chest Med. 2011;32:605–44. https://doi.org/10.1016/j.ccm.2011.09.001.
Ellinsworth DC. Arsenic, reactive oxygen, and endothelial dysfunction. J Pharmacol Exp Ther. 2015; https://doi.org/10.1124/jpet.115.223289.
Faita F, Cori L, Bianchi F, Andreassi MG. Arsenic-induced genotoxicity and genetic susceptibility to Arsenic-related pathologies. Int J Environ Res Public Health. 2013;10:1527–46. https://doi.org/10.3390/ijerph10041527.
Flora SJS. Arsenic-induced oxidative stress and its reversibility following combined administration of N-acetylcysteine and meso 2,3-dimercaptosuccinic acid in rats. Clin Exp Pharmacol Physiol. 1999;26:865–9. https://doi.org/10.1046/j.1440-1681.1999.03157.x.
Förstermann U, Münzel T. Endothelial nitric oxide synthase in vascular disease: from marvel to menace. Circulation. 2006; https://doi.org/10.1161/CIRCULATIONAHA.105.602532.
Fowler BA, Selene C-H, Chou R, Jones J, Dexter L, Sullivan W Jr, Chen C-J. Chapter 28 – Arsenic. In: Nordberg GF, Fowler BA, Nordberg M, editors. Handbook on the toxicology of metals. 4th ed. San Diego: Academic; 2015. p. 581–624. https://doi.org/10.1016/B978-0-444-59453-2.00028-7.
Frankenberg E. 基因的改变NIH public access. Bone. 2012;23:1–7. https://doi.org/10.1007/978-1-59745-416-2.
Gonzalez H, Lema C, Kirken R, Maldonado A, Varela-Ramirez A, Aguilera J. Arsenic-exposed keratinocytes exhibit differential microRNAs expression profile; potential implication of miR-21, miR-200a and miR-141 in melanoma pathway. Clin Cancer Drugs. 2015;2:138–47. https://doi.org/10.2174/2212697x02666150629174704.
Gozin A, Franzini E, Andrieu V, Da Costa L, Rollet-Labelle E, Pasquier C. Reactive oxygen species activate focal adhesion kinase, paxillin and P130CAS tyrosine phosphorylation in endothelial cells. Free Radic Biol Med. 1998; https://doi.org/10.1016/S0891-5849(98)00134-8.
Graves P, Zeng Y. Biogenesis of mammalian microRNAs: a global view. genomics. Proteomics Bioinf. 2012;10:239–45. https://doi.org/10.1016/j.gpb.2012.06.004.
Green DR, Kroemer G. Cytoplasmic functions of the tumour suppressor p53. Nature. 2009; https://doi.org/10.1038/nature07986.
Hegde ML, Hazra TK, Mitra S. Early steps in the DNA base excision/single-strand interruption repair pathway in mammalian cells. Cell Res. 2008;18:27–47. https://doi.org/10.1038/cr.2008.8.
Hei TK, Liu SUX, Waldren C. Mutagenicity of Arsenic in mammalian cells: role of reactive oxygen species. Proc Natl Acad Sci U S A. 1998; https://doi.org/10.1073/pnas.95.14.8103.
Heikens A. Arsenic contamination of irrigation water, soil and crops in Bangladesh: risk implications for sustainable agriculture and food safety in Asia. FAO – RAP Publications. 2006/20 20, 2; 2006.
Hinhumpatch P, Navasumrit P, Chaisatra K, Promvijit J, Mahidol C, Ruchirawat M. Oxidative DNA damage and repair in children exposed to low levels of Arsenic in utero and during early childhood: application of salivary and urinary biomarkers. Toxicol Appl Pharmacol. 2013;273 https://doi.org/10.1016/j.taap.2013.10.002.
Huang HW, Lee CH, Yu HS. Arsenic-induced carcinogenesis and immune dysregulation. Int J Environ Res Public Health. 2019:16. https://doi.org/10.3390/ijerph16152746.
Hug SJ, Leupin O. Iron-catalyzed oxidation of Arsenic(III) by oxygen and by hydrogen peroxide: pH-dependent formation of oxidants in the Fenton reaction. Environ Sci Technol. 2003;37:2734–42. https://doi.org/10.1021/es026208x.
Humphries B, Yang C. The microRNA-200 family: small molecules with novel roles in cancer development, progression and therapy. Oncotarget. 2015;6:6472–98. https://doi.org/10.18632/oncotarget.3052.
Kato K, Hayashi H, Hasegawa A, Yamanaka K, Okada S. DNA damage induced in cultured human alveolar (L-132) cells by exposure to dimethylarsinic acid. Environ Health Perspect. 1994; https://doi.org/10.1289/ehp.94102s3285.
Khairul I, Wang QQ, Jiang YH, Wang C, Naranmandura H. Metabolism, toxicity and anticancer activities of Arsenic compounds. Oncotarget. 2017;8:23905–26. https://doi.org/10.18632/oncotarget.14733.
Krammer PH. CD95(APO-1/Fas)-mediated apoptosis: live and let die. Adv Immunol. 1998; https://doi.org/10.1016/s0065-2776(08)60402-2.
Ledgerwood LG, Kumar D, Eterovic AK, Wick J, Chen K, Zhao H, Tazi L, Manna P, Kerley S, Joshi R, Wang L, Chiosea SI, Garnett JD, Tsue TT, Chien J, Mills GB, Grandis JR, Thomas SM. The degree of intratumor mutational heterogeneity varies by primary tumor sub-site. Oncotarget. 2016;7:27185–98. https://doi.org/10.18632/oncotarget.8448.
Lee TC, Tanaka N, Lamb PW, Gilmer TM, Barrett JC. Induction of gene amplification by Arsenic. Science. 1988;80 https://doi.org/10.1126/science.3388020.
Liao W-T, Lu J-H, Lee C-H, Lan C-CE, Chang J-G, Chai C-Y, Yu H-S. An interaction between Arsenic-induced epigenetic modification and inflammatory promotion in a skin equivalent during Arsenic carcinogenesis. J Invest Dermatol. 2017;137:187–96. https://doi.org/10.1016/j.jid.2016.08.017.
Liu J, Waalkes MP. Liver is a target of Arsenic carcinogenesis. Toxicol Sci. 2008;105:24–32. https://doi.org/10.1093/toxsci/kfn120.
Liu SX, Athar M, Lippai I, Waldren C, Hei TK. Induction of oxyradicals by Arsenic: implication for mechanism of genotoxicity. Proc Natl Acad Sci U S A. 2001; https://doi.org/10.1073/pnas.98.4.1643.
Ludwig S, Hoffmeyer A, Goebeler M, Kilian K, Häfner H, Neufeld B, Han J, Rapp UR. The stress inducer arsenite activates mitogen-activated protein kinases extracellular signal-regulated kinases 1 and 2 via a MAPK kinase 6/p38- dependent pathway. J Biol Chem. 1998;273:1917–22. https://doi.org/10.1074/jbc.273.4.1917.
Martindale JL, Holbrook NJ. Cellular response to oxidative stress: signaling for suicide and survival. J Cell Physiol. 2002; https://doi.org/10.1002/jcp.10119.
Martinez VD, Becker-Santos DD, Vucic EA, Lam S, Lam WL. Induction of human squamous cell-type carcinomas by Arsenic. J Skin Cancer. 2011a;2011:454157. https://doi.org/10.1155/2011/454157.
Martinez VD, Vucic EA, Adonis M, Gil L, Lam WL. Arsenic biotransformation as a cancer promoting factor by inducing DNA damage and disruption of repair mechanisms. Mol Biol Int. 2011b;2011:1–11. https://doi.org/10.4061/2011/718974.
Martinez VD, Vucic EA, Becker-Santos DD, Gil L, Lam WL. Arsenic exposure and the induction of human cancers. J Toxicol. 2011c;2011 https://doi.org/10.1155/2011/431287.
Masuda T, Ishii K, Morishita Y, Iwasaki N, Shibata Y, Tamaoka A. Hepatic histopathological changes and dysfunction in primates following exposure to organic Arsenic diphenylarsinic acid. J Toxicol Sci. 2018; https://doi.org/10.2131/jts.43.291.
Menzel DB, Rasmussen RE, Lee E, Meacher DM, Said B, Hamadeh H, Vargas M, Greene H, Roth RN. Human lymphocyte home oxygenase 1 as a response biomarker to inorganic Arsenic. Biochem Biophys Res Commun. 1998; https://doi.org/10.1006/bbrc.1998.9363.
Moore LE, Smith AH, Eng C, Kalman D, DeVries S, Bhargava V, Chew K, Moore D, Ferreccio C, Rey OA, Waldman FM. Arsenic-related chromosomal alterations in bladder cancer. J Natl Cancer Inst. 2002;94:1688–96. https://doi.org/10.1093/jnci/94.22.1688.
Muenyi CS, Ljungman M, States JC. Arsenic disruption of DNA damage responses-potential role in carcinogenesis and chemotherapy. Biomolecules. 2015;5:2184–93. https://doi.org/10.3390/biom5042184.
Naranmandura H, Xu S, Koike S, Pan LQ, Chen B, Wang YW, Rehman K, Wu B, Chen Z, Suzuki N. The endoplasmic reticulum is a target organelle for trivalent dimethylarsinic acid (DMA III)-induced cytotoxicity. Toxicol Appl Pharmacol. 2012;260:241–9. https://doi.org/10.1016/j.taap.2012.02.017.
Nordenson I, Beckman L. Is the genotoxic effect of Arsenic mediated by oxygen free radicals? Hum Hered. 1991;41:71–3. https://doi.org/10.1159/000153979.
O’Brien J, Hayder H, Zayed Y, Peng C. Overview of microRNA biogenesis, mechanisms of actions, and circulation. Front Endocrinol (Lausanne). 2018;9:402. https://doi.org/10.3389/fendo.2018.00402.
Oketani M, Kohara K, Tuvdendorj D, Ishitsuka K, Komorizono Y, Ishibashi K, Arima T. Inhibition by Arsenic trioxide of human hepatoma cell growth. Cancer Lett. 2002; https://doi.org/10.1016/S0304-3835(01)00800-X.
Page C. Arsenic toxicity. Encycl Met. 2013;143–143 https://doi.org/10.1007/978-1-4614-1533-6_100120.
Porter AC, Fanger GR, Vaillancourt RR. Signal transduction pathways regulated by arsenate and arsenite. Oncogene. 1999; https://doi.org/10.1038/sj.onc.1203214.
Rahman M, Vahter M, Wahed MA, Sohel N, Yunus M, Streatfield PK, El Arifeen S, Bhuiya A, Zaman K, Chowdhury AMR, Ekström EC, Persson LÅ. Prevalence of Arsenic exposure and skin lesions. A population based survey in Matlab, Bangladesh. J Epidemiol Community Health. 2006;60:242–8. https://doi.org/10.1136/jech.2005.040212.
Rahman MS, Kumar A, Kumar R, Ali M, Ghosh AK, Singh SK. Comparative quantification study of Arsenic in the groundwater and biological samples of Simri Village of Buxar District, Bihar, India. Indian J Occup Environ Med. 2019;23:126–32. https://doi.org/10.4103/ijoem.IJOEM_240_18.
Reichard JF, Puga A. Effects of Arsenic exposure on DNA methylation and epigenetic gene regulation. Epigenomics. 2010;2:87–104. https://doi.org/10.2217/epi.09.45.
Ren X, Gaile DP, Gong Z, Qiu W, Ge Y, Huang C, Yan H, Olson JR, Kavanagh TJ, Wu H, Professions H, Professions H, Sciences OH. HHS Public Access. 2016;283:198–209. https://doi.org/10.1016/j.taap.2015.01.014.Arsenic.
Riley T, Sontag E, Chen P, Levine A. Transcriptional control of human p53-regulated genes. Nat Rev Mol Cell Biol. 2008; https://doi.org/10.1038/nrm2395.
Rousseau MC, Straif K, Siemiatycki J. IARC carcinogen update [1]. Environ Health Perspect. 2005;113:580–3. https://doi.org/10.1289/ehp.113-a580.
Sablina AA, Budanov AV, Ilyinskaya GV, Agapova LS, Kravchenko JE, Chumakov PM. The antioxidant function of the p53 tumor suppressor. Nat Med. 2005; https://doi.org/10.1038/nm1320.
Shahid M, Dumat C, Niazi N, Khalid S, Natasha N. Global scale Arsenic pollution: increase the scientific knowledge to reduce human exposure. VertigO. 2018; https://doi.org/10.4000/vertigo.21331.
Tanriover B. Renal cell cancer, environmental Arsenic exposure and carcinogenic mutations. UHOD Uluslararasi Hematol Derg. 2012;22:62–6. https://doi.org/10.4999/uhod.11079.
Tchounwou P, Patlolla A, Centeno J. Carcinogenic and Systemic health effects associated with Arsenic exposure – a critical review. Toxicol Pathol. 2003;31:575–88. https://doi.org/10.1080/714044691.
Vahter M. Mechanisms of Arsenic biotransformation. Toxicology. 2002;181–182:211–7. https://doi.org/10.1016/s0300-483x(02)00285-8.
Vahter M, Concha G. Role of metabolism in Arsenic toxicity. Pharmacol Toxicol. 2001;89:1–5. https://doi.org/10.1034/j.1600-0773.2001.d01-128.x.
Vélez-Cruz R, Johnson DG. The retinoblastoma (RB) tumor suppressor: pushing back against genome instability on multiple fronts. Int J Mol Sci. 2017;18 https://doi.org/10.3390/ijms18081776.
Wu W, Jaspers I, Zhang W, Graves LM, Samet JM. Role of Ras in metal-induced EGF receptor signaling and NF-κB activation in human airway epithelial cells. Am J Phys Lung Cell Mol Phys. 2002:282. https://doi.org/10.1152/ajplung.00390.2001.
Yamamura S. Drinking water guidelines and standards. United Nations Synth Rep Arsen Drink Water. 2001:18.
Yamanaka K, Okada S. Induction of lung-specific DNA damage by metabolically methylated Arsenics via the production of free radicals. Environ Health Perspect. 1994; https://doi.org/10.1289/ehp.94102s337.
Yamanaka K, Hayashi H, Tachikawa M, Kato K, Hasegawa A, Oku N, Okada S. Metabolic methylation is a possible genotoxicity-enhancing process of inorganic Arsenics. Mutat Res Genet Toxicol Environ Mutagen. 1997;394:95–101. https://doi.org/10.1016/S1383-5718(97)00130-7.
Yamauchi H, Aminaka Y, Yoshida K, Sun G, Pi J, Waalkes M. Evaluation of DNA damage in patients with Arsenic poisoning: urinary 8-hydroxydeoxyguanine. Toxicol Appl Pharmacol. 2004;198:291–6. https://doi.org/10.1016/j.taap.2003.10.021.
Yeh S, How SW, Lin CS. Arsenical cancer of skin. Histologic study with special reference to Bowen’s disease. Cancer. 1968;21:312–39. https://doi.org/10.1002/1097-0142(196802)21:2<312::aid-cncr2820210222>3.0.co;2-k.
Yu H-S, Liao W-T, Chai C-Y. Arsenic carcinogenesis in the skin. J Biomed Sci. 2006;13:657–66. https://doi.org/10.1007/s11373-006-9092-8.
Zeng K, Zhong B, Fang M, Shen X-L, Huang L-N. Common polymorphisms of the hOGG1, APE1 and XRCC1 genes correlate with the susceptibility and clinicopathological features of primary angle-closure glaucoma. Biosci Rep. 2017;37 https://doi.org/10.1042/BSR20160644.
Zhang T, Yang Z, Kusumanchi P, Han S, Liangpunsakul S. Critical role of microRNA-21 in the pathogenesis of liver diseases. Front Med. 2020;7:1–7. https://doi.org/10.3389/fmed.2020.00007.
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James, S. et al. (2021). Role of Arsenic in Carcinogenesis. In: Kesari, K.K., Jha, N.K. (eds) Free Radical Biology and Environmental Toxicity. Molecular and Integrative Toxicology. Springer, Cham. https://doi.org/10.1007/978-3-030-83446-3_7
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