The Protective Effect of Cilostazol in Genotoxicity Induced by Methotrexate in Human Cultured Lymphocytes

Author(s): Abeer M. Rababa’h*, Samah A. Hussein, Omar F. Khabour, Karem H. Alzoubi

Journal Name: Current Molecular Pharmacology

Volume 13 , Issue 2 , 2020

DOI : 10.2174/1874467212666191023120118

  Journal Home
Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Methotrexate is an antagonist of folic acid that has been shown to be genotoxic to healthy body cells via induction of oxidative stress. Cilostazol is a phosphodiesterase III inhibitor and a potent antioxidant drug.

Objective: To evaluate the potential protective effect of cilostazol on methotrexate genotoxicity.

Methods: The genotoxic effect of methotrexate by measuring the frequency of chromosomal aberrations (CAs) and sister chromatid exchanges (SCEs) in human cultured lymphocytes was studied.

Results: Methotrexate significantly increased the frequency of CAs and SCEs (p < 0.0001) as compared to control cultures. This chromosomal damage induced by methotrexate was considerably decreased by pretreatment of the cells with cilostazol (P < 0.01). Moreover, the results showed that methotrexate resulted in a notable reduction (P < 0.01) in cells kinetic parameters, the mitotic index (MI) and the proliferative index (PI). Similarly, cilostazol significantly reduced the mitotic index, which could be related to the anti-proliferative effect (P < 0.01).

Conclusion: Methotrexate is genotoxic, and cilostazol could prevent the methotrexate-induced chromosomal damage with no modulation of methotrexate-induced cytotoxicity.

Keywords: Methotrexate, cilostazol, genotoxicity, chromosomal aberrations, sister chromatid exchanges.

[1]
Alarcóan, G.S.; Tracy, I.C.; Blackburn, W.D., Jr Methotrexate in rheumatoid arthritis. Toxic effects as the major factor in limiting long‐term treatment. Arthritis & Rheumatism. Official Journal of the American College of Rheumatology, 1989, 32(6), 671-676.
[2]
Shahin, A.A.; Ismail, M.M.; Saleh, A.M.; Moustafa, H.A.; Aboul-Ella, A.A.; Gabr, H.M. Protective effect of folinic acid on low-dose methotrexate genotoxicity. Z. Rheumatol., 2001, 60(2), 63-68.
[http://dx.doi.org/10.1007/s003930170075] [PMID: 11383050]
[3]
Taylor, O.A.; Hockenberry, M.J.; McCarthy, K.; Gundy, P.; Montgomery, D.; Ross, A.; Scheurer, M.E.; Moore, I.M. Evaluation of biomarkers of oxidative stress and apoptosis in patients with severe methotrexate neurotoxicity: a case series. J. Pediatr. Oncol. Nurs., 2015, 32(5), 320-325.
[http://dx.doi.org/10.1177/1043454214563409] [PMID: 25637187]
[4]
Deng, H.; Zhang, M.; He, J.; Wu, W.; Jin, L.; Zheng, W.; Lou, J.; Wang, B. Investigating genetic damage in workers occupationally exposed to methotrexate using three genetic end-points. Mutagenesis, 2005, 20(5), 351-357.
[http://dx.doi.org/10.1093/mutage/gei048] [PMID: 16037120]
[5]
Xie, L.; Zhao, T.; Cai, J.; Su, Y.; Wang, Z.; Dong, W. Methotrexate induces DNA damage and inhibits homologous recombination repair in choriocarcinoma cells. OncoTargets Ther., 2016, 9, 7115-7122.
[http://dx.doi.org/10.2147/OTT.S116387] [PMID: 27895503]
[6]
Shen, J.; Deininger, P.; Hunt, J.D.; Zhao, H. 8-Hydroxy-2′-deoxyguanosine (8-OH-dG) as a potential survival biomarker in patients with nonsmall-cell lung cancer. Cancer, 2007, 109(3), 574-580.
[http://dx.doi.org/10.1002/cncr.22417] [PMID: 17154177]
[7]
Martin, S.A.; McCarthy, A.; Barber, L.J.; Burgess, D.J.; Parry, S.; Lord, C.J.; Ashworth, A. Methotrexate induces oxidative DNA damage and is selectively lethal to tumour cells with defects in the DNA mismatch repair gene MSH2. EMBO Mol. Med., 2009, 1(6-7), 323-337.
[http://dx.doi.org/10.1002/emmm.200900040] [PMID: 20049736]
[8]
Cetinkaya, A.; Bulbuloglu, E.; Kurutas, E.B.; Kantarceken, B. N-acetylcysteine ameliorates methotrexate-induced oxidative liver damage in rats. Med. Sci. Monit., 2006, 12(8), BR274-BR278.
[PMID: 16865059]
[9]
Akbulut, S.; Elbe, H.; Eris, C.; Dogan, Z.; Toprak, G.; Otan, E.; Erdemli, E.; Turkoz, Y. Cytoprotective effects of amifostine, ascorbic acid and N-acetylcysteine against methotrexate-induced hepatotoxicity in rats. World J. Gastroenterol., 2014, 20(29), 10158-10165.
[http://dx.doi.org/10.3748/wjg.v20.i29.10158] [PMID: 25110444]
[10]
Abo-Haded, H.M.; Elkablawy, M.A.; Al-Johani, Z.; Al-Ahmadi, O.; El-Agamy, D.S. Hepatoprotective effect of sitagliptin against methotrexate induced liver toxicity. PLoS One, 2017, 12(3)e0174295
[http://dx.doi.org/10.1371/journal.pone.0174295] [PMID: 28334048]
[11]
Ashoka Ch, M.S.M. Antigenotoxic effects of rutin against methotrexate genotoxicity in Swiss albino mice. Curr. Trends Biotechnol. Pharm., 2019, 13(2), 163-177.
[12]
Bhogal, P.; Brouwer, P.A.; Makalanda, H.L. Cilostazol: an antiplatelet agent for the neurointerventionist? J. Neurointerv. Surg., 2016, 8(2), 208-209.
[http://dx.doi.org/10.1136/neurintsurg-2014-011570] [PMID: 25526917]
[13]
Bedenis, R. Cilostazol for intermittent claudication., 2014.
[http://dx.doi.org/10.1002/14651858.CD003748.pub4]
[14]
Rababa’h, A.M.; Mardini, A.N.; Alzoubi, K.H.; Ababneh, M.A.; Athamneh, R.Y. The effect of cilostazol on hippocampal memory and oxidative stress biomarkers in rat model of diabetes mellitus. Brain Res., 2019, 1715, 182-187.
[http://dx.doi.org/10.1016/j.brainres.2019.03.025] [PMID: 30914251]
[15]
Chattipakorn, S.C.; Thummasorn, S.; Sanit, J.; Chattipakorn, N. Phosphodiesterase-3 inhibitor (cilostazol) attenuates oxidative stress-induced mitochondrial dysfunction in the heart. J. Geriatr. Cardiol., 2014, 11(2), 151-157.
[PMID: 25009566]
[16]
Park, S.Y.; Lee, S.W.; Baek, S.H.; Lee, C.W.; Lee, W.S.; Rhim, B.Y.; Hong, K.W.; Kim, C.D. Suppression of PU.1-linked TLR4 expression by cilostazol with decrease of cytokine production in macrophages from patients with rheumatoid arthritis. Br. J. Pharmacol., 2013, 168(6), 1401-1411.
[http://dx.doi.org/10.1111/bph.12021] [PMID: 23072581]
[17]
Khabour, O.F.; Enaya, F.M.; Alzoubi, K.; Al-Azzam, S.I. Evaluation of DNA damage induced by norcantharidin in human cultured lymphocytes. Drug Chem. Toxicol., 2016, 39(3), 303-306.
[http://dx.doi.org/10.3109/01480545.2015.1113988] [PMID: 26599593]
[18]
Vitale, L.; Serpieri, V.; Lauriola, M.; Piovesan, A.; Antonaros, F.; Cicchini, E.; Locatelli, C.; Cocchi, G.; Strippoli, P.; Caracausi, M. Human trisomy 21 fibroblasts rescue methotrexate toxic effect after treatment with 5-methyl-tetrahydrofolate and 5-formyl-tetrahydrofolate. J. Cell. Physiol., 2019.
[http://dx.doi.org/10.1002/jcp.28140] [PMID: 30667057]
[19]
Aoki, C.; Hattori, Y.; Tomizawa, A.; Jojima, T.; Kasai, K. Anti-inflammatory role of cilostazol in vascular smooth muscle cells in vitro and in vivo. J. Atheroscler. Thromb., 2010, 17(5), 503-509.
[http://dx.doi.org/10.5551/jat.3392] [PMID: 20179359]
[20]
Sadiq, M.F.; Khabour, O.F.; el-Shanti, H.E.; Samawi, H.M. The effect of trifluoperazine on the genotoxicity of bleomycin in cultured human lymphocytes. Drug Chem. Toxicol., 2000, 23(2), 361-369.
[http://dx.doi.org/10.1081/DCT-100100121] [PMID: 10826102]
[21]
Alqudah, M.A.Y.; Al-Ashwal, F.Y.; Alzoubi, K.H.; Alkhatatbeh, M.; Khabour, O. Vitamin E protects human lymphocytes from genotoxicity induced by oxaliplatin. Drug Chem. Toxicol., 2018, 41(3), 281-286.
[http://dx.doi.org/10.1080/01480545.2017.1384835] [PMID: 29092638]
[22]
Al-Sweedan, S.A.; Khabour, O.; Isam, R. Genotoxicity assessment in patients with thalassemia minor. Mutat. Res., 2012, 744(2), 167-171.
[http://dx.doi.org/10.1016/j.mrgentox.2012.02.010] [PMID: 22414564]
[23]
Wolff, S.; Afzal, V. Segregation of DNA polynucleotide strands into sister chromatids and the use of endoreduplicated cells to track sister chromatid exchanges induced by crosslinks, alkylations, or x-ray damage. Proc. Natl. Acad. Sci. USA, 1996, 93(12), 5765-5769.
[http://dx.doi.org/10.1073/pnas.93.12.5765] [PMID: 8650167]
[24]
M’Bemba-Meka, P.; Lemieux, N.; Chakrabarti, S.K. Role of oxidative stress and intracellular calcium in nickel carbonate hydroxide-induced sister-chromatid exchange, and alterations in replication index and mitotic index in cultured human peripheral blood lymphocytes. Arch. Toxicol., 2007, 81(2), 89-99.
[http://dx.doi.org/10.1007/s00204-006-0128-7] [PMID: 16826409]
[25]
Alzoubi, K.; Khabour, O.; Khader, M.; Mhaidat, N.; Al-Azzam, S. Evaluation of vitamin B12 effects on DNA damage induced by paclitaxel. Drug Chem. Toxicol., 2014, 37(3), 276-280.
[http://dx.doi.org/10.3109/01480545.2013.851686] [PMID: 24215581]
[26]
Norppa, H.; Bonassi, S.; Hansteen, I.L.; Hagmar, L.; Strömberg, U.; Rössner, P.; Boffetta, P.; Lindholm, C.; Gundy, S.; Lazutka, J.; Cebulska-Wasilewska, A.; Fabiánová, E.; Srám, R.J.; Knudsen, L.E.; Barale, R.; Fucic, A. Chromosomal aberrations and SCEs as biomarkers of cancer risk. Mutat. Res., 2006, 600(1-2), 37-45.
[http://dx.doi.org/10.1016/j.mrfmmm.2006.05.030] [PMID: 16814813]
[27]
Bonassi, S.; Hagmar, L.; Strömberg, U.; Montagud, A.H.; Tinnerberg, H.; Forni, A.; Heikkilä, P.; Wanders, S.; Wilhardt, P.; Hansteen, I.L.; Knudsen, L.E.; Norppa, H. Chromosomal aberrations in lymphocytes predict human cancer independently of exposure to carcinogens. Cancer Res., 2000, 60(6), 1619-1625.
[PMID: 10749131]
[28]
Mahmoodi, M.; Soleyman-Jahi, S.; Zendehdel, K.; Mozdarani, H.; Azimi, C.; Farzanfar, F.; Safari, Z.; Mohagheghi, M.A.; Khaleghian, M.; Divsalar, K.; Asgari, E.; Rezaei, N. Chromosomal aberrations, sister chromatid exchanges, and micronuclei in lymphocytes of oncology department personnel handling anti-neoplastic drugs. Drug Chem. Toxicol., 2017, 40(2), 235-240.
[http://dx.doi.org/10.1080/01480545.2016.1209678] [PMID: 27461518]
[29]
Mondello, C.; Giorgi, R.; Nuzzo, F. Chromosomal effects of methotrexate on cultured human lymphocytes. Mutat. Res., 1984, 139(2), 67-70.
[http://dx.doi.org/10.1016/0165-7992(84)90105-2] [PMID: 6694664]
[30]
Atteritano, M.; Mazzaferro, S.; Mantuano, S.; Bagnato, G.L.; Bagnato, G.F. Effects of infliximab on sister chromatid exchanges and chromosomal aberration in patients with rheumatoid arthritis. Cytotechnology, 2016, 68(2), 313-318.
[http://dx.doi.org/10.1007/s10616-014-9782-4] [PMID: 26012953]
[31]
Gu, S.; Wu, Y.; Yang, J. Screening of cytoprotectors against methotrexate-induced cytogenotoxicity from bioactive phytochemicals. PeerJ, 2016, 4e1983
[http://dx.doi.org/10.7717/peerj.1983] [PMID: 27190706]
[32]
Said Salem, N.I.; Noshy, M.M.; Said, A.A. Modulatory effect of curcumin against genotoxicity and oxidative stress induced by cisplatin and methotrexate in male mice. Food Chem. Toxicol., 2017, 105, 370-376.
[http://dx.doi.org/10.1016/j.fct.2017.04.007] [PMID: 28428088]
[33]
Fujiwara, Y.; Banno, H.; Shinkai, Y.; Yamamoto, C.; Kaji, T.; Satoh, M. Protective effect of pretreatment with cilostazol on cytotoxicity of cadmium and arsenite in cultured vascular endothelial cells. J. Toxicol. Sci., 2011, 36(2), 155-161.
[http://dx.doi.org/10.2131/jts.36.155] [PMID: 21467742]
[34]
Kim, H.Y.; Lee, S.W.; Park, S.Y.; Baek, S.H.; Lee, C.W.; Hong, K.W.; Kim, C.D. Efficacy of concurrent administration of cilostazol and methotrexate in rheumatoid arthritis: pharmacologic and clinical significance. Life Sci., 2012, 91(7-8), 250-257.
[http://dx.doi.org/10.1016/j.lfs.2012.07.003] [PMID: 22820172]
[35]
Rogers, K.C.; Oliphant, C.S.; Finks, S.W. Clinical efficacy and safety of cilostazol: a critical review of the literature. Drugs, 2015, 75(4), 377-395.
[http://dx.doi.org/10.1007/s40265-015-0364-3] [PMID: 25758742]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 13
ISSUE: 2
Year: 2020
Published on: 26 April, 2020
Page: [137 - 143]
Pages: 7
DOI: 10.2174/1874467212666191023120118
Price: $65

Article Metrics

PDF: 16
HTML: 3



Most Downloaded Article(s)