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Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

Cellular and DNA Toxicity Study of Triphenyltin Ethyl Phenyl Dithiocarbamate and Triphenyltin Butyl Phenyl Dithiocarbamate on K562, Leukemia Cell Line

Author(s): Asmah Hamid*, Nor Fadilah Rajab, Yip Charmagne, Normah Awang, Nurul Farhana Jufri and Nur Rasyiqin Rasli

Volume 24, Issue 1, 2024

Published on: 30 October, 2023

Page: [58 - 65] Pages: 8

DOI: 10.2174/0118715206266851231025054446

Price: $65

Abstract

Introduction: Continuous research for new effective drugs to treat cancer has improved our understanding on the mechanism of action of these drugs and paved new potential for their application in cancer treatments. In this study, organotin compounds known as triphenyltin ethyl phenyl dithiocarbamate and triphenyltin butyl phenyl dithiocarbamate were investigated for their toxicity on leukemia cell line (K562) and non-cancerous cell line (Chang liver cell and lung fibroblast, V79 cell).

Methods: MTT assay was performed to evaluate the cytotoxic effects of both compounds toward the cells after 24, 48 and 72 hours of exposure or treatment. The alkaline comet assay was conducted to determine the DNA damage on K562 cells after been exposed to both compounds for 30, 60 and 90 minutes.

Results: The IC50 values obtained from K562 cells ranged from 0.01 to 0.30 μM, whereas for both Chang liver cell and lung fibroblast V79 cell, the values ranged from 0.10 to 0.40 μM. For genotoxicity evaluation, the percentage of damaged DNA is measured as an average of tail moment, and was found to be within 1.20 to 2.20 A.U while the percentage of DNA intensity ranging from 1.50 to 3.50% indicating no genotoxic effects.

Conclusion: Both compounds are cytotoxic toward leukemia cells and non-cancerous cells but do not exert their genotoxic effects towards leukemia cell.

Keywords: Organotin, triphenyltin, leukemia, cytotoxic, DNA damage, K562.

Graphical Abstract
[1]
Zylbersztejn, F.; Flores-Violante, M.; Voeltzel, T.; Nicolini, F.E.; Lefort, S.; Maguer-Satta, V. The BMP pathway: A unique tool to decode the origin and progression of leukemia. Exp. Hematol., 2018, 61, 36-44.
[http://dx.doi.org/10.1016/j.exphem.2018.02.005] [PMID: 29477370]
[2]
Kassahun, W.; Tesfaye, G.; Bimerew, LG.; Fufa, D.; Adissu, W.; Yemane, T. Prevalence of leukemia and associated factors among patients with abnormal hematological parameters in Jimma Medical Center, Southwest Ethiopia: A cross-sectional study. Adv. Hematol. 2020, 2020.
[http://dx.doi.org/10.1155/2020/2014152]
[3]
Loscocco, F.; Visani, G.; Galimberti, S.; Curti, A.; Isidori, A. BCR-ABL independent mechanisms of resistance in chronic myeloid leukemia. Front. Oncol., 2019, 9, 939.
[http://dx.doi.org/10.3389/fonc.2019.00939] [PMID: 31612105]
[4]
Amarante-Mendes, G.P.; Rana, A.; Datoguia, T.S.; Hamerschlak, N.; Brumatti, G. BCR-ABL1 tyrosine kinase complex signaling transduction: challenges to overcome resistance in chronic myeloid leukemia. Pharmaceutics, 2022, 14(1), 215.
[http://dx.doi.org/10.3390/pharmaceutics14010215] [PMID: 35057108]
[5]
Nickoloff, J.A. Targeting replication stress response pathways to enhance genotoxic chemo-and radiotherapy. Molecules, 2022, 27(15), 4736.
[http://dx.doi.org/10.3390/molecules27154736] [PMID: 35897913]
[6]
Lang, F.; Liu, Y.; Chou, F.J.; Yang, C. Genotoxic therapy and resistance mechanism in gliomas. Pharmacol. Ther., 2021, 228, 107922.
[http://dx.doi.org/10.1016/j.pharmthera.2021.107922] [PMID: 34171339]
[7]
Çiftçiler, R.; Haznedaroglu, I.C. Tailored tyrosine kinase inhibitor (TKI) treatment of chronic myeloid leukemia (CML) based on current evidence. Eur. Rev. Med. Pharmacol. Sci., 2021, 25(24), 7787-7798.
[PMID: 34982440]
[8]
García-Gutiérrez, V.; Breccia, M.; Jabbour, E.; Mauro, M.; Cortes, J.E. A clinician perspective on the treatment of chronic myeloid leukemia in the chronic phase. J. Hematol. Oncol., 2022, 15(1), 90.
[http://dx.doi.org/10.1186/s13045-022-01309-0] [PMID: 35818053]
[9]
Genthon, A.; Nicolini, F.E.; Huguet, F.; Colin-Gil, C.; Berger, M.; Saugues, S.; Janel, A.; Hayette, S.; Cohny-Makhoul, P.; Cadoux, N.; Cayuela, J.M.; Campos, L.; Guyotat, D.; Flandrin-Gresta, P. Influence of major BCR-ABL1 transcript subtype on outcome in patients with chronic myeloid leukemia in chronic phase treated frontline with nilotinib. Oncotarget, 2020, 11(26), 2560-2570.
[http://dx.doi.org/10.18632/oncotarget.27652] [PMID: 32655840]
[10]
Breccia, M.; Alimena, G. Second-generation tyrosine kinase inhibitors (TKI) as salvage therapy for resistant or intolerant patients to prior tkis. Mediterr. J. Hematol. Infect. Dis., 2014, 6(1), e2014003.
[http://dx.doi.org/10.4084/mjhid.2014.003] [PMID: 24455112]
[11]
Mehri, A. Trace elements in human nutrition (II)–an update. Int. J. Prev. Med., 2020, 11, 2.
[PMID: 32042399]
[12]
Ovejero, P. K.; Díaz-García, D.; García-Almodóvar, V.; Lozano Chamizo, L.; Marciello, M.; Díaz-Sánchez, M.; Prashar, S.; Gómez-Ruiz, S.; Filice, M. Multifunctional silica-based nanoparticles with controlled release of organotin metallodrug for targeted theranosis of breast cancer. Cancers, 2020, 12(1), 187.
[http://dx.doi.org/10.3390/cancers12010187] [PMID: 31940937]
[13]
Graisa, A.M.; Husain, A.A.; Al-Mashhadani, M.H.; Ahmed, D.S.; Adil, H.; Yousif, E. The organotin applications in biological, industrial and agricultural sectors: A systematic review. J. Serambi Eng., 2022, 7(1)
[14]
Zhang, S.; Li, P.; Li, Z.H. Toxicity of organotin compounds and the ecological risk of organic tin with co-existing contaminants in aquatic organisms. Comp. Biochem. Physiol. C Toxicol. Pharmacol., 2021, 246, 109054.
[http://dx.doi.org/10.1016/j.cbpc.2021.109054] [PMID: 33887478]
[15]
Chen, C.; Chen, L.; Xue, R.; Huang, Q.; Wu, L.; Ye, S.; Zhang, W. Spatiotemporal variation and source apportionment of organotin compounds in sediments in the Yangtze Estuary. Environ. Sci. Eur., 2019, 31, 1-9.
[16]
Nur Adibah, M.A. Synthesis, characterization and encapsulation studies of multidentate ligands and their organotin complexes / Nur Adibah Mohd Amin.. Masters thesis, University of Malaya 2019.
[17]
Arraq, R.R.; Hadi, A.G. Enhanced the antioxidant activity of tri organotin (IV) complexes derived from cephalexin. Azerbaijan Med. J. 2022, 2022.
[18]
Ajiboye, T.O.; Ajiboye, T.T.; Marzouki, R.; Onwudiwe, D.C. The versatility in the applications of dithiocarbamates. Int. J. Mol. Sci., 2022, 23(3), 1317.
[http://dx.doi.org/10.3390/ijms23031317] [PMID: 35163241]
[19]
Bansal, O. Health impacts of the carbamate and dithiocarbamate pesticides: A review. Int. J. Sci. Res. Publ., 2022, 12(2)
[http://dx.doi.org/10.29322/IJSRP.12.02.2022.p12250]
[20]
Abd Aziz, N.A.; Awang, N.; Chan, K.M.; Kamaludin, N.F.; Anuar, N.N.M. Organotin (IV) dithiocarbamate compounds as anticancer agents: A review of syntheses and cytotoxicity studies. Molecules, 2023, 28(15), 5841.
[21]
Rasli, N.R.; Hamid, A.; Awang, N.; Kamaludin, N.F. Series of organotin(IV) compounds with different dithiocarbamate ligands induced cytotoxicity, apoptosis and cell cycle arrest on jurkat E6.1, T acute lymphoblastic leukemia cells. Molecules, 2023, 28(8), 3376.
[http://dx.doi.org/10.3390/molecules28083376] [PMID: 37110610]
[22]
Sirajuddin, M.; Ali, S.; Tahir, M.N. Organotin(IV) derivatives based on 2-((2-methoxyphenyl)carbamoyl)benzoic acid: Synthesis, spectroscopic characterization, assessment of antibacterial, DNA interaction, anticancer and antileishmanial potentials. J. Mol. Struct., 2021, 1229, 129600.
[http://dx.doi.org/10.1016/j.molstruc.2020.129600]
[23]
Hamid, A.; Azmi, M.A.; Rajab, N.F.; Awang, N.; Jufri, N.F. Cytotoxic effects of organotin(IV) dithiocarbamate compounds with different functional groups on leukemic cell line, K-562. Sains Malays., 2020, 49(6), 1421-1430.
[http://dx.doi.org/10.17576/jsm-2020-4906-20]
[24]
Devi, J.; Boora, A.; Rani, M.; Arora, T. Recent advancements in organotin (IV) complexes as potent cytotoxic agents. Anti-Cancer. Agents Med. Chem., 2023, 23, 164-191.
[25]
Awang, N.; Kamaludin, N.F. Cytotoxicity of diphenyltin(IV) diisopropyl dithiocarbamate compound on acute lymphoblastic leukemia cells, CCL-119 (CCRF-CEM). Preprints, 2022, 2022050149.
[http://dx.doi.org/10.20944/preprints202205.0149.v1]
[26]
Kamaludin, N.F.; Awang, N. Synthesis and characterisation of organotin (IV) N-ethyl-N-phenyldithiocarbamate compounds and the crystal structures of dibutyl-and triphenyltin (IV) N-ethyl-N-phenyldithiocarbamate. Res. J. Chem. Environ., 2014, 18, 99-107.
[27]
Mosmann, T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J. Immunol. Methods, 1983, 65(1-2), 55-63.
[http://dx.doi.org/10.1016/0022-1759(83)90303-4] [PMID: 6606682]
[28]
Singh, N.P.; McCoy, M.T.; Tice, R.R.; Schneider, E.L. A simple technique for quantitation of low levels of DNA damage in individual cells. Exp. Cell Res., 1988, 175(1), 184-191.
[http://dx.doi.org/10.1016/0014-4827(88)90265-0] [PMID: 3345800]
[29]
Antonenko, T.A.; Gracheva, Y.A.; Shpakovsky, D.B.; Vorobyev, M.A.; Mazur, D.M.; Tafeenko, V.A.; Oprunenko, Y.F.; Shevtsova, E.F.; Shevtsov, P.N.; Nazarov, A.A.; Milaeva, E.R. Biological activity of novel organotin compounds with a schiff base containing an antioxidant fragment. Int. J. Mol. Sci., 2023, 24(3), 2024.
[http://dx.doi.org/10.3390/ijms24032024] [PMID: 36768345]
[30]
Mandal, A.; Ghosh, M.; Talukdar, D.; Dey, P.; Das, A.; Giri, S. Cytotoxicity and genotoxicity of tributyltin in the early embryonic chick, Gallus gallus domesticus. Mutat. Res. Genet. Toxicol. Environ. Mutagen., 2023, 889, 503656.
[http://dx.doi.org/10.1016/j.mrgentox.2023.503656] [PMID: 37491115]
[31]
Syed Annuar, S.N.; Kamaludin, N.F.; Awang, N.; Chan, K.M. Triphenyltin(IV) dithiocarbamate compound induces genotoxicity and cytotoxicity in K562 human erythroleukemia cells primarily via mitochondria-mediated apoptosis. Food Chem. Toxicol., 2022, 168, 113336.
[http://dx.doi.org/10.1016/j.fct.2022.113336] [PMID: 35963475]
[32]
Hunakova, L.; Macejova, D.; Toporova, L.; Brtko, J. Anticancer effects of tributyltin chloride and triphenyltin chloride in human breast cancer cell lines MCF-7 and MDA-MB-231. Tumour Biol., 2016, 37(5), 6701-6708.
[http://dx.doi.org/10.1007/s13277-015-4524-6] [PMID: 26662104]
[33]
Sirajuddin, M.; Ali, S.; McKee, V.; Sohail, M.; Pasha, H. Potentially bioactive organotin(IV) compounds: Synthesis, characterization, in vitro bioactivities and interaction with SS-DNA. Eur. J. Med. Chem., 2014, 84, 343-363.
[http://dx.doi.org/10.1016/j.ejmech.2014.07.028] [PMID: 25036793]
[34]
Adeyemi, J.; Onwudiwe, D. Antimicrobial and cytotoxicity studies of some organotin (IV) N-ethyl-N-phenyl dithiocarbamate complexes. Pol. J. Environ. Stud., 2020, 29(4), 2525-2532.
[http://dx.doi.org/10.15244/pjoes/111231]
[35]
Golonko, A.; Olichwier, A.J.; Swislocka, R.; Szczerbinski, L.; Lewandowski, W. Why do dietary flavonoids have a promising effect as enhancers of anthracyclines? hydroxyl substituents, bioavailability and biological activity. Int. J. Mol. Sci., 2022, 24(1), 391.
[http://dx.doi.org/10.3390/ijms24010391] [PMID: 36613834]
[36]
Niu, L.; Li, Y.; Li, Q. Medicinal properties of organotin compounds and their limitations caused by toxicity. Inorg. Chim. Acta, 2014, 423, 2-13.
[http://dx.doi.org/10.1016/j.ica.2014.05.007]
[37]
Zhou, M.; Feng, M.; Fu, L.; Ji, L.; Zhao, J.; Xu, J. Toxicogenomic analysis identifies the apoptotic pathway as the main cause of hepatotoxicity induced by tributyltin. Food Chem. Toxicol., 2016, 97, 316-326.
[http://dx.doi.org/10.1016/j.fct.2016.09.027] [PMID: 27678064]
[38]
Kumar, M.; Abbas, Z.; Siwach, P.; Sharma, J.; Rani, A.; Sharma, S.; Aggarwal, P.; Show, P-L.; Haque, S. Path of organotin complexes: Synthetic factors, mechanisms, and broad-spectrum biological influences. J. Adv. Biotechnol. Exp Ther., 2023, 6(2), 386-402.
[39]
Damghani, T.; Moosavi, F.; Khoshneviszadeh, M.; Mortazavi, M.; Pirhadi, S.; Kayani, Z.; Saso, L.; Edraki, N.; Firuzi, O. Imidazopyridine hydrazone derivatives exert antiproliferative effect on lung and pancreatic cancer cells and potentially inhibit receptor tyrosine kinases including c-Met. Sci. Rep., 2021, 11(1), 3644.
[http://dx.doi.org/10.1038/s41598-021-83069-4] [PMID: 33574356]
[40]
Ullah, H.; Previtali, V.; Mihigo, H.B.; Twamley, B.; Rauf, M.K.; Javed, F.; Waseem, A.; Baker, R.J.; Rozas, I. Structure-activity relationships of new Organotin(IV) anticancer agents and their cytotoxicity profile on HL-60, MCF-7 and HeLa human cancer cell lines. Eur. J. Med. Chem., 2019, 181, 111544.
[http://dx.doi.org/10.1016/j.ejmech.2019.07.047] [PMID: 31374420]
[41]
Koch, A.; Tamez, P.; Pezzuto, J.; Soejarto, D. Evaluation of plants used for antimalarial treatment by the Maasai of Kenya. J. Ethnopharmacol., 2005, 101(1-3), 95-99.
[http://dx.doi.org/10.1016/j.jep.2005.03.011] [PMID: 15878245]
[42]
Kim, K.; Yoo, H.J.; Jung, J.H.; Lee, R.; Hyun, J.K.; Park, J.H.; Na, D.; Yeon, J.H. Cytotoxic effects of plant sap-derived extracellular vesicles on various tumor cell types. J. Funct. Biomater., 2020, 11(2), 22.
[http://dx.doi.org/10.3390/jfb11020022] [PMID: 32252412]
[43]
Hamid, A.; Aiyelaagbe, O.; Usman, L.; Ameen, O.; Lawal, A. Antioxidants: Its medicinal and pharmacological applications. Afr. J. Pure Appl. Chem., 2010, 4, 142-151.
[44]
Seebacher, N.A.; Richardson, D.R.; Jansson, P.J. A mechanism for overcoming P-glycoprotein-mediated drug resistance: Novel combination therapy that releases stored doxorubicin from lysosomes via lysosomal permeabilization using Dp44mT or DpC. Cell Death Dis., 2016, 7(12), e2510-e2510.
[http://dx.doi.org/10.1038/cddis.2016.381] [PMID: 27906178]
[45]
Kairuki, M.; Qiu, Q.; Pan, M.; Li, Q.; Zhou, J.; Ghaleb, H.; Huang, W.; Qian, H.; Jiang, C. Designed P-glycoprotein inhibitors with triazol-tetrahydroisoquinoline-core increase doxorubicin-induced mortality in multidrug resistant K562/A02 cells. Bioorg. Med. Chem., 2019, 27(15), 3347-3357.
[http://dx.doi.org/10.1016/j.bmc.2019.06.013] [PMID: 31202598]
[46]
Farahana Kamaludin, N.; Aishah Zakaria, S.; Awang, N.; Mohamad, R.; Uttraphan Pim, N. Cytotoxicity assessment of organotin (IV)(2-metoxyethyl) methyldithiocarbamate compounds in human leukemia cell lines. Orient. J. Chem., 2017, 33(4), 1756-1766.
[http://dx.doi.org/10.13005/ojc/330420]
[47]
Ray, D.; Sarma, K.D.; Antony, A. Differential effects of tri-n-butylstannyl benzoates on induction of apoptosis in K562 and MCF-7 cells. IUBMB Life, 2000, 49(6), 519-525.
[http://dx.doi.org/10.1080/15216540050167061] [PMID: 11032246]
[48]
Pantelić, NĐ; Zmejkovski, BB; Žižak, Ž; Banjac, NR; Božić, BĐ; Stanojković, TP; Kaluđerović, GN Design and in vitro biological evaluation of a novel organotin (IV) complex with 1-(4-carboxyphenyl)-3-ethyl-3-methylpyrrolidine-2, 5-dione. J. Chem. 2019, 2019.
[49]
Syed Annuar, S.N.; Kamaludin, N.F.; Awang, N.; Chan, K.M.; Uttraphan Pim, N. Diorganotin(IV) N-methyl-N-phenethyldithio-carbamate compounds induce cytotoxicity via apoptosis in K562 human erythroleukaemia cells. Sains Malays., 2023, 52(5), 1513-1521.
[http://dx.doi.org/10.17576/jsm-2023-5205-14]
[50]
Sit, K.H.; Bay, B.H.; Wong, K.P. Reduced surface area in mitotic rounding of human chang liver cells. Anat. Rec., 1993, 235(2), 183-190.
[http://dx.doi.org/10.1002/ar.1092350202] [PMID: 8420388]
[51]
Jiang, N.; Naz, S.; Ma, Y.; Ullah, Q.; Khan, M.Z.; Wang, J.; Lu, X.; Luosang, D.Z.; Tabassum, S.; Chatha, A.M.M.; Basang, W-D. An overview of comet assay application for detecting DNA damage in aquatic animals. Agriculture, 2023, 13(3), 623.
[http://dx.doi.org/10.3390/agriculture13030623]
[52]
Gajski, G. Ravlić, S.; Godschalk, R.; Collins, A.; Dusinska, M.; Brunborg, G. Application of the comet assay for the evaluation of DNA damage in mature sperm. Mutat. Res. Rev. Mutat. Res., 2021, 788, 108398.
[http://dx.doi.org/10.1016/j.mrrev.2021.108398] [PMID: 34893163]
[53]
Møller, P.; Stopper, H.; Collins, A.R. Measurement of DNA damage with the comet assay in high-prevalence diseases: Current status and future directions. Mutagenesis, 2020, 35(1), 5-18.
[PMID: 31294794]
[54]
Rodríguez, R.; Gaivão, I.; Aguado, L.; Espina, M.; García, J.; Martínez-Camblor, P.; Sierra, L.M. The comet assay in drosophila: A tool to study interactions between DNA repair systems in DNA damage responses in vivo and ex vivo. Cells, 2023, 12(15), 1979.
[http://dx.doi.org/10.3390/cells12151979] [PMID: 37566058]
[55]
Kuchařová, M.; Hronek, M.; Rybáková, K.; Zadák, Z.; Štětina, R.; Josková, V.; Patková, A. Comet assay and its use for evaluating oxidative DNA damage in some pathological states. Physiol. Res., 2019, 68(1), 1-15.
[http://dx.doi.org/10.33549/physiolres.933901] [PMID: 30433808]
[56]
Alhmoud, J.F.; Woolley, J.F.; Al Moustafa, A.E.; Malki, M.I. DNA damage/repair management in cancers. Cancers, 2020, 12(4), 1050.
[http://dx.doi.org/10.3390/cancers12041050] [PMID: 32340362]
[57]
Awang, N.; Kamaludin, N.F.; Hamid, A.; Mokhtar, N.W.N.; Rajab, N.F. Cytotoxicity of triphenyltin(IV) methyl- and ethylisopropyldithiocarbamate compounds in chronic myelogenus leukemia cell line (K-562). Pak. J. Biol. Sci., 2012, 15(17), 833-838.
[http://dx.doi.org/10.3923/pjbs.2012.833.838] [PMID: 24163967]
[58]
Rostami, A.; Lambie, M.; Yu, C.W.; Stambolic, V.; Waldron, J.N.; Bratman, S.V. Senescence, necrosis, and apoptosis govern circulating cell-free DNA release kinetics. Cell Rep., 2020, 31(13), 107830.
[http://dx.doi.org/10.1016/j.celrep.2020.107830] [PMID: 32610131]
[59]
Sun, Z.; Xue, L.; Li, Y.; Cui, G.; Sun, R.; Hu, M.; Zhong, G. Rotenone-induced necrosis in insect cells via the cytoplasmic membrane damage and mitochondrial dysfunction. Pestic. Biochem. Physiol., 2021, 173, 104801.
[http://dx.doi.org/10.1016/j.pestbp.2021.104801] [PMID: 33771250]
[60]
Chigasova, A.K.; Ostrovskaya, L.A.; Korman, D.B. Induction of DNA structure damage in tumor cells by gold polyacrylate. Biophysics (Oxf.), 2023, 68(1), 6-12.
[http://dx.doi.org/10.1134/S0006350923010050]
[61]
Sharif, R.; Ghazali, A.R.; Rajab, N.F. DNA damaging effect of selected salted and fermented food products against chang liver cell. Jurnal Sains Kesihatan Malaysia, 2007, 5, 63-77.

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