Melatonin a Promising Candidate for DNA Double-Stranded Breaks Reduction in Patients Undergoing Abdomen-Pelvis Computed Tomography Examinations

Author(s): Ali Eskandari, Aziz Mahmoudzadeh, Alireza Shirazi, Farid Esmaely, Carla Carnovale, Mohsen Cheki*

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 20 , Issue 7 , 2020

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Graphical Abstract:


Abstract:

Background and Objective: Cancer incidence is 24% higher in children and young adults exposed to Computed Tomography (CT) scans than those unexposed. Non-repairing of ionizing radiation-induced DNA Double-Strand Breaks (DSBs) can initiate carcinogenesis. In the present study, we aimed to investigate the radioprotective potential of melatonin against DSBs in peripheral blood lymphocytes of patients undergoing abdomen-pelvis CT examinations.

Methods: This double-blind, placebo-controlled clinical trial was conducted on thirty patients. These patients were divided into two groups; group one (control) patients who have undergone the CT examination received a single oral dose of placebo, while in group two, patients received a single oral dose of 100mg melatonin. In both the groups, blood samples were collected 5-10min before and 30 minutes after the CT examination. The lymphocytes from these samples were isolated and DSBs were analyzed using γH2AX immunofluorescence microscopy.

Results: Compared to the control group, the use of melatonin 1h before the CT examination caused a significant reduction in γH2AX-foci, indicating a reduction in DSBs. In addition, no side effect was observed in patients following 100mg melatonin administration.

Conclusion: For the first time, this study has shown that melatonin has protective effects against radiationinduced genotoxicity in peripheral blood lymphocytes of patients undergoing abdomen-pelvis CT examinations. Therefore, melatonin can be considered as a promising candidate for reducing DSBs in patients undergoing abdomen-pelvis CT examinations.

Keywords: Melatonin, γH2AX, lymphocytes, computed tomography, radiation, DSB.

[1]
Hounsfield, G.N. Computerized transverse axial scanning (tomography). 1. Description of system. Br. J. Radiol., 1973, 46(552), 1016-1022.
[http://dx.doi.org/10.1259/0007-1285-46-552-1016] [PMID: 4757352]
[2]
Berrington de González, A.; Darby, S. Risk of cancer from diagnostic X-rays: estimates for the UK and 14 other countries. Lancet, 2004, 363(9406), 345-351.
[http://dx.doi.org/10.1016/S0140-6736(04)15433-0] [PMID: 15070562]
[3]
Berrington de González, A.; Mahesh, M.; Kim, K-P.; Bhargavan, M.; Lewis, R.; Mettler, F.; Land, C. Projected cancer risks from computed tomographic scans performed in the United States in 2007. Arch. Intern. Med., 2009, 169(22), 2071-2077.
[http://dx.doi.org/10.1001/archinternmed.2009.440] [PMID: 20008689]
[4]
Fazel, R.; Krumholz, H.M.; Wang, Y.; Ross, J.S.; Chen, J.; Ting, H.H.; Shah, N.D.; Nasir, K.; Einstein, A.J.; Nallamothu, B.K. Exposure to low-dose ionizing radiation from medical imaging procedures. N. Engl. J. Med., 2009, 361(9), 849-857.
[http://dx.doi.org/10.1056/NEJMoa0901249] [PMID: 19710483]
[5]
Brand, M.; Sommer, M.; Achenbach, S.; Anders, K.; Lell, M.; Löbrich, M.; Uder, M.; Kuefner, M.A. X-ray induced DNA double-strand breaks in coronary CT angiography: comparison of sequential, low-pitch helical and high-pitch helical data acquisition. Eur. J. Radiol., 2012, 81(3), e357-e362.
[http://dx.doi.org/10.1016/j.ejrad.2011.11.027] [PMID: 22178288]
[6]
Kuefner, M.A.; Grudzenski, S.; Hamann, J.; Achenbach, S.; Lell, M.; Anders, K.; Schwab, S.A.; Häberle, L.; Löbrich, M.; Uder, M. Effect of CT scan protocols on x-ray-induced DNA double-strand breaks in blood lymphocytes of patients undergoing coronary CT angiography. Eur. Radiol., 2010, 20(12), 2917-2924.
[http://dx.doi.org/10.1007/s00330-010-1873-9] [PMID: 20625737]
[7]
Kuefner, M.A.; Grudzenski, S.; Schwab, S.A.; Wiederseiner, M.; Heckmann, M.; Bautz, W.; Lobrich, M.; Uder, M. DNA double-strand breaks and their repair in blood lymphocytes of patients undergoing angiographic procedures. Invest. Radiol., 2009, 44(8), 440-446.
[http://dx.doi.org/10.1097/RLI.0b013e3181a654a5] [PMID: 19448553]
[8]
Mettler, F.A., Jr; Thomadsen, B.R.; Bhargavan, M.; Gilley, D.B.; Gray, J.E.; Lipoti, J.A.; McCrohan, J.; Yoshizumi, T.T.; Mahesh, M. Medical radiation exposure in the U.S. in 2006: preliminary results. Health Phys., 2008, 95(5), 502-507.
[http://dx.doi.org/10.1097/01.HP.0000326333.42287.a2] [PMID: 18849682]
[9]
Watson, J.D.; Crick, F.H. A structure for deoxyribose nucleic acid. 1953. Nature, 2003, 421(6921), 397-398.
[PMID: 12569935]
[10]
Löbrich, M.; Rief, N.; Kühne, M.; Heckmann, M.; Fleckenstein, J.; Rübe, C.; Uder, M. In vivo formation and repair of DNA double-strand breaks after computed tomography examinations. Proc. Natl. Acad. Sci. USA, 2005, 102(25), 8984-8989.
[http://dx.doi.org/10.1073/pnas.0501895102] [PMID: 15956203]
[11]
van Gent, D.C.; Hoeijmakers, J.H.; Kanaar, R. Chromosomal stability and the DNA double-stranded break connection. Nat. Rev. Genet., 2001, 2(3), 196-206.
[http://dx.doi.org/10.1038/35056049] [PMID: 11256071]
[12]
Jeggo, P.A.; Löbrich, M. DNA double-strand breaks: their cellular and clinical impact? Oncogene, 2007, 26(56), 7717-7719.
[http://dx.doi.org/10.1038/sj.onc.1210868] [PMID: 18066083]
[13]
Löbrich, M.; Jeggo, P.A. The impact of a negligent G2/M checkpoint on genomic instability and cancer induction. Nat. Rev. Cancer, 2007, 7(11), 861-869.
[http://dx.doi.org/10.1038/nrc2248] [PMID: 17943134]
[14]
Löbrich, M.; Shibata, A.; Beucher, A.; Fisher, A.; Ensminger, M.; Goodarzi, A.A.; Barton, O.; Jeggo, P.A. gammaH2AX foci analysis for monitoring DNA double-strand break repair: strengths, limitations and optimization. Cell Cycle, 2010, 9(4), 662-669.
[http://dx.doi.org/10.4161/cc.9.4.10764] [PMID: 20139725]
[15]
Rogakou, E.P.; Boon, C.; Redon, C.; Bonner, W.M. Megabase chromatin domains involved in DNA double-strand breaks in vivo. J. Cell Biol., 1999, 146(5), 905-916.
[http://dx.doi.org/10.1083/jcb.146.5.905] [PMID: 10477747]
[16]
Rothkamm, K.; Löbrich, M. Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray doses. Proc. Natl. Acad. Sci. USA, 2003, 100(9), 5057-5062.
[http://dx.doi.org/10.1073/pnas.0830918100] [PMID: 12679524]
[17]
Kuefner, M.A.; Hinkmann, F.M.; Alibek, S.; Azoulay, S.; Anders, K.; Kalender, W.A.; Achenbach, S.; Grudzenski, S.; Löbrich, M.; Uder, M. Reduction of X-ray induced DNA double-strand breaks in blood lymphocytes during coronary CT angiography using high-pitch spiral data acquisition with prospective ECG-triggering. Invest. Radiol., 2010, 45(4), 182-187.
[http://dx.doi.org/10.1097/RLI.0b013e3181d3eddf] [PMID: 20177387]
[18]
Pearce, M.S.; Salotti, J.A.; Little, M.P.; McHugh, K.; Lee, C.; Kim, K.P.; Howe, N.L.; Ronckers, C.M.; Rajaraman, P.; Sir Craft, A.W.; Parker, L.; Berrington de González, A. Radiation exposure from CT scans in childhood and subsequent risk of leukaemia and brain tumours: a retrospective cohort study. Lancet, 2012, 380(9840), 499-505.
[http://dx.doi.org/10.1016/S0140-6736(12)60815-0] [PMID: 22681860]
[19]
Puig, Á.; Rancan, L.; Paredes, S.D.; Carrasco, A.; Escames, G.; Vara, E.; Tresguerres, J.A. Melatonin decreases the expression of inflammation and apoptosis markers in the lung of a senescence-accelerated mice model. Exp. Gerontol., 2016, 75, 1-7.
[http://dx.doi.org/10.1016/j.exger.2015.11.021] [PMID: 26656745]
[20]
Tan, D-X.; Manchester, L.C.; Esteban-Zubero, E.; Zhou, Z.; Reiter, R.J. Melatonin as a potent and inducible endogenous antioxidant: Synthesis and metabolism. Molecules, 2015, 20(10), 18886-18906.
[http://dx.doi.org/10.3390/molecules201018886] [PMID: 26501252]
[21]
Zetner, D.; Andersen, L.P.; Rosenberg, J. Melatonin as protection against radiation injury: A systematic review. Drug Res. (Stuttg.), 2016, 66(6), 281-296.
[http://dx.doi.org/10.1055/s-0035-1569358] [PMID: 26789653]
[22]
Karbownik, M.; Reiter, R.J. Antioxidative effects of melatonin in protection against cellular damage caused by ionizing radiation. Proc. Soc. Exp. Biol. Med., 2000, 225(1), 9-22.
[http://dx.doi.org/10.1046/j.1525-1373.2000.22502.x] [PMID: 10998194]
[23]
Shirazi, A.; Ghobadi, G.; Ghazi-Khansari, M. A radiobiological review on melatonin: a novel radioprotector. J. Radiat. Res. (Tokyo), 2007, 48(4), 263-272.
[http://dx.doi.org/10.1269/jrr.06070] [PMID: 17641465]
[24]
Rogakou, E.P.; Pilch, D.R.; Orr, A.H.; Ivanova, V.S.; Bonner, W.M. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J. Biol. Chem., 1998, 273(10), 5858-5868.
[http://dx.doi.org/10.1074/jbc.273.10.5858] [PMID: 9488723]
[25]
Brenner, D.J.; Doll, R.; Goodhead, D.T.; Hall, E.J.; Land, C.E.; Little, J.B.; Lubin, J.H.; Preston, D.L.; Preston, R.J.; Puskin, J.S.; Ron, E.; Sachs, R.K.; Samet, J.M.; Setlow, R.B.; Zaider, M. Cancer risks attributable to low doses of ionizing radiation: assessing what we really know. Proc. Natl. Acad. Sci. USA, 2003, 100(24), 13761-13766.
[http://dx.doi.org/10.1073/pnas.2235592100] [PMID: 14610281]
[26]
Mathews, J.D.; Forsythe, A.V.; Brady, Z.; Butler, M.W.; Goergen, S.K.; Byrnes, G.B.; Giles, G.G.; Wallace, A.B.; Anderson, P.R.; Guiver, T.A.; McGale, P.; Cain, T.M.; Dowty, J.G.; Bickerstaffe, A.C.; Darby, S.C. Cancer risk in 680,000 people exposed to computed tomography scans in childhood or adolescence: data linkage study of 11 million Australians. BMJ, 2013, 346, f2360.
[http://dx.doi.org/10.1136/bmj.f2360] [PMID: 23694687]
[27]
Karslioğlu, I.; Ertekin, M.V.; Taysi, S.; Koçer, I.; Sezen, O.; Gepdiremen, A.; Koç, M.; Bakan, N. Radioprotective effects of melatonin on radiation-induced cataract. J. Radiat. Res. (Tokyo), 2005, 46(2), 277-282.
[http://dx.doi.org/10.1269/jrr.46.277] [PMID: 15988147]
[28]
Erol, F.S.; Topsakal, C.; Ozveren, M.F.; Kaplan, M.; Ilhan, N.; Ozercan, I.H.; Yildiz, O.G. Protective effects of melatonin and vitamin E in brain damage due to gamma radiation: an experimental study. Neurosurg. Rev., 2004, 27(1), 65-69.
[http://dx.doi.org/10.1007/s10143-003-0291-8] [PMID: 12955582]
[29]
El-Missiry, M.A.; Fayed, T.A.; El-Sawy, M.R.; El-Sayed, A.A. Ameliorative effect of melatonin against gamma-irradiation-induced oxidative stress and tissue injury. Ecotoxicol. Environ. Saf., 2007, 66(2), 278-286.
[http://dx.doi.org/10.1016/j.ecoenv.2006.03.008] [PMID: 16793135]
[30]
Taysi, S.; Koc, M.; Büyükokuroğlu, M.E.; Altinkaynak, K.; Şahin, Y.N. Melatonin reduces lipid peroxidation and nitric oxide during irradiation-induced oxidative injury in the rat liver. J. Pineal Res., 2003, 34(3), 173-177.
[http://dx.doi.org/10.1034/j.1600-079X.2003.00024.x] [PMID: 12614476]
[31]
Sharma, S.; Haldar, C. Melatonin prevents X-ray irradiation induced oxidative damagein peripheral blood and spleen of the seasonally breeding rodent, Funambulus pennanti during reproductively active phase. Int. J. Radiat. Biol., 2006, 82(6), 411-419.
[http://dx.doi.org/10.1080/09553000600774105] [PMID: 16846976]
[32]
Sharma, S.; Haldar, C.; Chaube, S.K.; Laxmi, T.; Singh, S.S. Long-term melatonin administration attenuates low-LET γ-radiation-induced lymphatic tissue injury during the reproductively active and inactive phases of Indian palm squirrels (Funambulus pennanti). Br. J. Radiol., 2010, 83(986), 137-151.
[http://dx.doi.org/10.1259/bjr/73791461] [PMID: 20139262]
[33]
Sharma, S.; Haldar, C.; Chaube, S.K. Effect of exogenous melatonin on X-ray induced cellular toxicity in lymphatic tissue of Indian tropical male squirrel, Funambulus pennanti. Int. J. Radiat. Biol., 2008, 84(5), 363-374.
[http://dx.doi.org/10.1080/09553000802029894] [PMID: 18464066]
[34]
Shabeeb, D.; Najafi, M.; Musa, A.E.; Keshavarz, M.; Shirazi, A.; Hassanzadeh, G.; Hadian, M.R.; Samandari, H. Biochemical and histopathological evaluation of the radioprotective effects of melatonin against gamma ray-induced skin damage. Curr. Radiopharm., 2019, 12(1), 72-81.
[http://dx.doi.org/10.2174/1874471012666181120163250] [PMID: 30465519]
[35]
Najafi, M.; Cheki, M.; Hassanzadeh, G.; Amini, P.; Shabeeb, D.; Eleojo,, M.A. Protection from radiation-induced damage in rat’s ileum and colon by combined regimens of melatonin and metformin: A histopathological study. Antiinflamm. Antiallergy Agents Med. Chem., 2020, 19, 1-10.
[36]
Shabeeb, D.; Najafi, M.; Keshavarz, M.; Musa, A.E.; Hassanzadeh, G.; Hadian, M.R.; Shirazi, A. Recent finding in repair of theperipheral nerve lesions using pharmacological agents: Commonmethods for evaluating the repair process. Central Nervous Syst.Agents Med. Chem. (Formerly Curr. Med. Chem.-Central NervousSyst. Agents), 2018, 18(3), 161-172.
[37]
Reiter, R.J.; Herman, T.S.; Meltz, M.L. Melatonin and radioprotection from genetic damage: In vivo/in vitro studies with human volunteers. Mutation Res. Genetic Toxicol., 1996, 371(3-4), 221-228.
[38]
Rostami, A.; Moosavi, S.A.; Dianat Moghadam, H.; Bolookat, E.R. Micronuclei Assessment of the radioprotective effects of melatonin and vitamin c in human lymphocytes. Cell J., 2016, 18(1), 46-51.
[PMID: 27054118]
[39]
Brand, M.; Sommer, M.; Ellmann, S.; Wuest, W.; May, M.S.; Eller, A.; Vogt, S.; Lell, M.M.; Kuefner, M.A.; Uder, M. Influence of different antioxidants on X-ray induced DNA Double-Strand Breaks (DSBs) using γ-H2AX immunofluorescence microscopy in a preliminary study. PLoS One, 2015, 10(5), e0127142
[http://dx.doi.org/10.1371/journal.pone.0127142] [PMID: 25996998]
[40]
Rothkamm, K. Different means to an end: DNA double-strand break repair., Life Sciences and Radiation; Springer, 2004.
[http://dx.doi.org/10.1007/978-3-642-18687-5_15]


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VOLUME: 20
ISSUE: 7
Year: 2020
Page: [859 - 864]
Pages: 6
DOI: 10.2174/1871521409666200324101701
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