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Current Molecular Pharmacology

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ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

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Research Article

The Psychiatric Drug Lithium Increases DNA Damage and Decreases Cell Survival in MCF-7 and MDA-MB-231 Breast Cancer Cell Lines Expos ed to Ionizing Radiation

Author(s): Maryam Rouhani*, Samira Ramshini and Maryam Omidi

Volume 12, Issue 4, 2019

Page: [301 - 310] Pages: 10

DOI: 10.2174/1874467212666190503151753

Price: $65

Abstract

Background: Breast cancer is the most common cancer among women. Radiation therapy is used for treating almost every stage of breast cancer. A strategy to reduce irradiation side effects and to decrease the recurrence of cancer is concurrent use of radiation and radiosensitizers. We studied the effect of the antimanic drug lithium on radiosensitivity of estrogen-receptor (ER)-positive MCF-7 and ER-negative, invasive, and radioresistant MDA-MB-231 breast cancer cell lines.

Methods: MCF-7 and MDA-MB-231 breast cancer cell lines were treated with 30 mM and 20 mM concentrations of lithium chloride (LiCl), respectively. These concentrations were determined by MTT viability assay. Growth curves were depicted and comet assay was performed for control and LiCl-treated cells after exposure to X-ray. Total and phosphorylated inactive levels of glycogen synthase kinase-3beta (GSK-3β) protein were determined by ELISA assay for control and treated cells.

Results: Treatment with LiCl decreased cell proliferation after exposure to X-ray as indicated by growth curves of MCF-7 and MDA-MB-231 cell lines within six days following radiation. Such treatment increased the amount of DNA damages represented by percent DNA in Tails of comets at 0, 1, 4, and even 24 hours after radiation in both studied cell lines. The amount of active GSK-3β was increased in LiCl-treated cells in ER-positive and ER-negative breast cancer cell lines.

Conclusion: Treatment with LiCl that increased the active GSK-3β protein, increased DNA damages and decreased survival independent of estrogen receptor status in breast cancer cells exposed to ionizing radiation.

Keywords: Lithium, breast cancer, radiosensitizer, DNA damage, glycogen synthase kinase-3 beta, ionizing radiation.

Graphical Abstract

[1]
Ferlay, J.; Soerjomataram, I.; Dikshit, R.; Eser, S.; Mathers, C.; Rebelo, M.; Parkin, D.M.; Forman, D.; Bray, F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer, 2015, 136(5), E359-E386.
[http://dx.doi.org/10.1002/ijc.29210] [PMID: 25220842]
[2]
Langlands, F.E.; Horgan, K.; Dodwell, D.D.; Smith, L. Breast cancer subtypes: Response to radiotherapy and potential radiosensitisation. Br. J. Radiol., 2013, 86(1023)20120601
[http://dx.doi.org/10.1259/bjr.20120601] [PMID: 23392193]
[3]
Chen, H.H.W.; Kuo, M.T. Improving radiotherapy in cancer treatment: Promises and challenges. Oncotarget, 2017, 8(37), 62742-62758.
[http://dx.doi.org/10.18632/oncotarget.18409] [PMID: 28977985]
[4]
Wang, H.; Mu, X.; He, H.; Zhang, X.D. Cancer Radiosensitizers. Trends Pharmacol. Sci., 2018, 39(1), 24-48.
[http://dx.doi.org/10.1016/j.tips.2017.11.003] [PMID: 29224916]
[5]
Marie-Egyptienne, D.T.; Lohse, I.; Hill, R.P. Cancer stem cells, the epithelial to mesenchymal transition (EMT) and radioresistance: potential role of hypoxia. Cancer Lett., 2013, 341(1), 63-72.
[http://dx.doi.org/10.1016/j.canlet.2012.11.019] [PMID: 23200673]
[6]
Chang, J.C. Cancer stem cells: Role in tumor growth, recurrence, metastasis, and treatment resistance. Medicine (Baltimore), 2016, 95(1)(Suppl. 1), S20-S25.
[http://dx.doi.org/10.1097/MD.0000000000004766] [PMID: 27611935]
[7]
Sharma, R.A.; Plummer, R.; Stock, J.K.; Greenhalgh, T.A.; Ataman, O.; Kelly, S.; Clay, R.; Adams, R.A.; Baird, R.D.; Billingham, L.; Brown, S.R.; Buckland, S.; Bulbeck, H.; Chalmers, A.J.; Clack, G.; Cranston, A.N.; Damstrup, L.; Ferraldeschi, R.; Forster, M.D.; Golec, J.; Hagan, R.M.; Hall, E.; Hanauske, A.R.; Harrington, K.J.; Haswell, T.; Hawkins, M.A.; Illidge, T.; Jones, H.; Kennedy, A.S.; McDonald, F.; Melcher, T.; O’Connor, J.P.; Pollard, J.R.; Saunders, M.P.; Sebag-Montefiore, D.; Smitt, M.; Staffurth, J.; Stratford, I.J.; Wedge, S.R. NCRI CTRad Academia- Pharma Joint Working Group. Clinical development of new drug-radiotherapy combinations. Nat. Rev. Clin. Oncol., 2016, 13(10), 627-642.
[http://dx.doi.org/10.1038/nrclinonc.2016.79] [PMID: 27245279]
[8]
Sneader, W. Drug discovery: a history; Wiley: Hoboken, N.J., 2005.
[http://dx.doi.org/10.1002/0470015535]
[9]
Manji, H.K.; Moore, G.J.; Chen, G. Lithium at 50: have the neuroprotective effects of this unique cation been overlooked? Biol. Psychiatry, 1999, 46(7), 929-940.
[http://dx.doi.org/10.1016/S0006-3223(99)00165-1] [PMID: 10509176]
[10]
Lyman, G.H.; Williams, C.C.; Preston, D.; Goldman, A.; Dinwoodie, W.R.; Saba, H.; Hartmann, R.; Jensen, R.; Shukovsky, L. Lithium carbonate in patients with small cell lung cancer receiving combination chemotherapy. Am. J. Med., 1981, 70(6), 1222-1229.
[http://dx.doi.org/10.1016/0002-9343(81)90831-7] [PMID: 6263091]
[11]
Gallicchio, V.S.; Chen, M.G.; Watts, T.D. Ability of lithium to accelerate the recovery of granulopoiesis after subacute radiation injury. Acta Radiol. Oncol., 1984, 23(5), 361-366.
[http://dx.doi.org/10.3109/02841868409136034] [PMID: 6209924]
[12]
Hager, E.D.; Dziambor, H.; Winkler, P.; Höhmann, D.; Macholdt, K. Effects of lithium carbonate on hematopoietic cells in patients with persistent neutropenia following chemotherapy or radiotherapy. J. Trace Elem. Med. Biol., 2002, 16(2), 91-97.
[http://dx.doi.org/10.1016/S0946-672X(02)80034-7] [PMID: 12195731]
[13]
Ballin, A.; Aladjem, M.; Banyash, M.; Boichis, H.; Barzilay, Z.; Gal, R.; Witz, I.P. The effect of lithium chloride on tumour appearance and survival of melanoma-bearing mice. Br. J. Cancer, 1983, 48(1), 83-87.
[http://dx.doi.org/10.1038/bjc.1983.160] [PMID: 6191768]
[14]
Beyaert, R.; Vanhaesebroeck, B.; Suffys, P.; Van Roy, F.; Fiers, W. Lithium chloride potentiates tumor necrosis factor-mediated cytotoxicity in vitro and in vivo. Proc. Natl. Acad. Sci. USA, 1989, 86(23), 9494-9498.
[http://dx.doi.org/10.1073/pnas.86.23.9494] [PMID: 2556714]
[15]
Greenblatt, D.Y.; Ndiaye, M.; Chen, H.; Kunnimalaiyaan, M. Lithium inhibits carcinoid cell growth in vitro. Am. J. Transl. Res., 2010, 2(3), 248-253.
[PMID: 20589165]
[16]
Kaufmann, L.; Marinescu, G.; Nazarenko, I.; Thiele, W.; Oberle, C.; Sleeman, J.; Blattner, C. LiCl induces TNF-α and FasL production, thereby stimulating apoptosis in cancer cells. Cell Commun. Signal., 2011, 9, 15.
[http://dx.doi.org/10.1186/1478-811X-9-15] [PMID: 21609428]
[17]
Li, H.; Huang, K.; Liu, X.; Liu, J.; Lu, X.; Tao, K.; Wang, G.; Wang, J. Lithium chloride suppresses colorectal cancer cell survival and proliferation through ROS/GSK-3β/NF-κB signaling pathway. Oxid. Med. Cell. Longev., 2014.2014241864
[http://dx.doi.org/10.1155/2014/241864] [PMID: 25002914]
[18]
Nowicki, M.O.; Dmitrieva, N.; Stein, A.M.; Cutter, J.L.; Godlewski, J.; Saeki, Y.; Nita, M.; Berens, M.E.; Sander, L.M.; Newton, H.B.; Chiocca, E.A.; Lawler, S. Lithium inhibits invasion of glioma cells; possible involvement of glycogen synthase kinase-3. Neuro-oncol., 2008, 10(5), 690-699.
[http://dx.doi.org/10.1215/15228517-2008-041] [PMID: 18715951]
[19]
Costabile, V.; Duraturo, F.; Delrio, P.; Rega, D.; Pace, U.; Liccardo, R.; Rossi, G.B.; Genesio, R.; Nitsch, L.; Izzo, P.; De Rosa, M. Lithium chloride induces mesenchymal-to-epithelial reverting transition in primary colon cancer cell cultures. Int. J. Oncol., 2015, 46(5), 1913-1923.
[http://dx.doi.org/10.3892/ijo.2015.2911] [PMID: 25738332]
[20]
Maeng, Y.S.; Lee, R.; Lee, B.; Choi, S.I.; Kim, E.K. Lithium inhibits tumor lymphangiogenesis and metastasis through the inhibition of TGFBIp expression in cancer cells. Sci. Rep., 2016, 6, 20739.
[http://dx.doi.org/10.1038/srep20739] [PMID: 26857144]
[21]
Stambolic, V.; Ruel, L.; Woodgett, J.R. Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells. Curr. Biol., 1996, 6(12), 1664-1668.
[http://dx.doi.org/10.1016/S0960-9822(02)70790-2] [PMID: 8994831]
[22]
Klein, P.S.; Melton, D.A. A molecular mechanism for the effect of lithium on development. Proc. Natl. Acad. Sci. USA, 1996, 93(16), 8455-8459.
[http://dx.doi.org/10.1073/pnas.93.16.8455] [PMID: 8710892]
[23]
Ryves, W.J.; Harwood, A.J. Lithium inhibits glycogen synthase kinase-3 by competition for magnesium. Biochem. Biophys. Res. Commun., 2001, 280(3), 720-725.
[http://dx.doi.org/10.1006/bbrc.2000.4169] [PMID: 11162580]
[24]
Jope, R.S. Anti-bipolar therapy: mechanism of action of lithium. Mol. Psychiatry, 1999, 4(2), 117-128.
[http://dx.doi.org/10.1038/sj.mp.4000494] [PMID: 10208444]
[25]
Chalecka-Franaszek, E.; Chuang, D.M. Lithium activates the serine/threonine kinase Akt-1 and suppresses glutamate-induced inhibition of Akt-1 activity in neurons. Proc. Natl. Acad. Sci. USA, 1999, 96(15), 8745-8750.
[http://dx.doi.org/10.1073/pnas.96.15.8745] [PMID: 10411946]
[26]
Kirshenboim, N.; Plotkin, B.; Shlomo, S.B.; Kaidanovich-Beilin, O.; Eldar-Finkelman, H. Lithium-mediated phosphorylation of glycogen synthase kinase-3beta involves PI3 kinase-dependent activation of protein kinase C-alpha. J. Mol. Neurosci., 2004, 24(2), 237-245.
[http://dx.doi.org/10.1385/JMN:24:2:237] [PMID: 15456937]
[27]
Gustin, J.P.; Karakas, B.; Weiss, M.B.; Abukhdeir, A.M.; Lauring, J.; Garay, J.P.; Cosgrove, D.; Tamaki, A.; Konishi, H.; Konishi, Y.; Mohseni, M.; Wang, G.; Rosen, D.M.; Denmeade, S.R.; Higgins, M.J.; Vitolo, M.I.; Bachman, K.E.; Park, B.H. Knockin of mutant PIK3CA activates multiple oncogenic pathways. Proc. Natl. Acad. Sci. USA, 2009, 106(8), 2835-2840.
[http://dx.doi.org/10.1073/pnas.0813351106] [PMID: 19196980]
[28]
McCubrey, J.A.; Steelman, L.S.; Bertrand, F.E.; Davis, N.M.; Sokolosky, M.; Abrams, S.L.; Montalto, G.; D’Assoro, A.B.; Libra, M.; Nicoletti, F.; Maestro, R.; Basecke, J.; Rakus, D.; Gizak, A.; Demidenko, Z.N.; Cocco, L.; Martelli, A.M.; Cervello, M. GSK-3 as potential target for therapeutic intervention in cancer. Oncotarget, 2014, 5(10), 2881-2911.
[http://dx.doi.org/10.18632/oncotarget.2037] [PMID: 24931005]
[29]
Maurer, U.; Preiss, F.; Brauns-Schubert, P.; Schlicher, L.; Charvet, C. GSK-3 - at the crossroads of cell death and survival. J. Cell Sci., 2014, 127(Pt 7), 1369-1378.
[http://dx.doi.org/10.1242/jcs.138057] [PMID: 24687186]
[30]
Takahashi-Yanaga, F.; Sasaguri, T. GSK-3beta regulates cyclin D1 expression: A new target for chemotherapy. Cell. Signal., 2008, 20(4), 581-589.
[http://dx.doi.org/10.1016/j.cellsig.2007.10.018] [PMID: 18023328]
[31]
Watcharasit, P.; Bijur, G.N.; Zmijewski, J.W.; Song, L.; Zmijewska, A.; Chen, X.; Johnson, G.V.; Jope, R.S. Direct, activating interaction between glycogen synthase kinase-3beta and p53 after DNA damage. Proc. Natl. Acad. Sci. USA, 2002, 99(12), 7951-7955.
[http://dx.doi.org/10.1073/pnas.122062299] [PMID: 12048243]
[32]
Hall, E.J.; Giaccia, A.J. Radiobiology for the radiologist, 6th ed; Lippincott Williams & Wilkins: Philadelphia, 2006.
[33]
Levenson, A.S.; Jordan, V.C. MCF-7: the first hormone-responsive breast cancer cell line. Cancer Res., 1997, 57(15), 3071-3078.
[PMID: 9242427]
[34]
Gordon, L.A.; Mulligan, K.T.; Maxwell-Jones, H.; Adams, M.; Walker, R.A.; Jones, J.L. Breast cell invasive potential relates to the myoepithelial phenotype. Int. J. Cancer, 2003, 106(1), 8-16.
[http://dx.doi.org/10.1002/ijc.11172] [PMID: 12794751]
[35]
Speers, C.; Zhao, S.; Liu, M.; Bartelink, H.; Pierce, L.J.; Feng, F.Y. Development and Validation of a Novel Radiosensitivity Signature in Human Breast Cancer. Clin. Cancer Res., 2015, 21(16), 3667-3677.
[http://dx.doi.org/10.1158/1078-0432.CCR-14-2898] [PMID: 25904749]
[36]
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]
[37]
Buch, K.; Peters, T.; Nawroth, T.; Sänger, M.; Schmidberger, H.; Langguth, P. Determination of cell survival after irradiation via clonogenic assay versus multiple MTT Assay--a comparative study. Radiat. Oncol., 2012, 7, 1.
[http://dx.doi.org/10.1186/1748-717X-7-1] [PMID: 22214341]
[38]
Chung, D.M.; Kim, J.H.; Kim, J.K. Evaluation of MTT and Trypan Blue assays for radiation-induced cell viability test in HepG2 cells. Int. J. Radiat. Res., 2015, 13, 331-335.
[39]
Strober, W. Trypan Blue Exclusion Test of Cell Viability. Curr. Protoc. Immunol.,, 2015.111, A3 B 1-3..
[http://dx.doi.org/10.1002/0471142735.ima03bs111]
[40]
Pu, X.; Wang, Z.; Klaunig, J.E. Alkaline Comet Assay for Assessing DNA Damage in Individual Cells. Curr. Protoc. Toxicol, 2015.65, 3 12 1-11..
[http://dx.doi.org/10.1002/0471140856.tx0312s65]
[41]
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]
[42]
Kumaravel, T.S.; Jha, A.N. Reliable Comet assay measurements for detecting DNA damage induced by ionising radiation and chemicals. Mutat. Res., 2006, 605(1-2), 7-16.
[http://dx.doi.org/10.1016/j.mrgentox.2006.03.002] [PMID: 16621680]
[43]
Roux, M.; Dosseto, A. From direct to indirect lithium targets: a comprehensive review of omics data. Metallomics, 2017, 9(10), 1326-1351.
[http://dx.doi.org/10.1039/C7MT00203C] [PMID: 28885630]
[44]
Welshons, W.V.; Engler, K.S.; Taylor, J.A.; Grady, L.H.; Curran, E.M. Lithium-stimulated proliferation and alteration of phosphoinositide metabolites in MCF-7 human breast cancer cells. J. Cell. Physiol., 1995, 165(1), 134-144.
[http://dx.doi.org/10.1002/jcp.1041650116] [PMID: 7559794]
[45]
Suganthi, M.; Sangeetha, G.; Gayathri, G.; Ravi Sankar, B. Biphasic dose-dependent effect of lithium chloride on survival of human hormone-dependent breast cancer cells (MCF-7). Biol. Trace Elem. Res., 2012, 150(1-3), 477-486.
[http://dx.doi.org/10.1007/s12011-012-9510-x] [PMID: 23054864]
[46]
Erguven, M.; Oktem, G.; Kara, A.N.; Bilir, A. Lithium chloride has a biphasic effect on prostate cancer stem cells and a proportional effect on midkine levels. Oncol. Lett., 2016, 12(4), 2948-2955.
[http://dx.doi.org/10.3892/ol.2016.4946] [PMID: 27703531]
[47]
Taherian, A.; Mazoochi, T. Different Expression of Extracellular Signal-Regulated Kinases (ERK) 1/2 and Phospho-Erk Proteins in MBA-MB-231 and MCF-7 Cells after Chemotherapy with Doxorubicin or Docetaxel. Iran. J. Basic Med. Sci., 2012, 15(1), 669-677.
[PMID: 23493035]
[48]
Jia, T.; Zhang, L.; Duan, Y.; Zhang, M.; Wang, G.; Zhang, J.; Zhao, Z. The differential susceptibilities of MCF-7 and MDA-MB-231 cells to the cytotoxic effects of curcumin are associated with the PI3K/Akt-SKP2-Cip/Kips pathway. Cancer Cell Int., 2014, 14(1), 126.
[http://dx.doi.org/10.1186/s12935-014-0126-4] [PMID: 25530715]
[49]
Khasraw, M.; Ashley, D.; Wheeler, G.; Berk, M. Using lithium as a neuroprotective agent in patients with cancer. BMC Med., 2012, 10, 131.
[http://dx.doi.org/10.1186/1741-7015-10-131] [PMID: 23121766]
[50]
Yazlovitskaya, E.M.; Edwards, E.; Thotala, D.; Fu, A.; Osusky, K.L.; Whetsell, W.O., Jr; Boone, B.; Shinohara, E.T.; Hallahan, D.E. Lithium treatment prevents neurocognitive deficit resulting from cranial irradiation. Cancer Res., 2006, 66(23), 11179-11186.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-2740] [PMID: 17145862]
[51]
Bhattacharjee, D.; Rajan, R.; Krishnamoorthy, L.; Singh, B.B. Effects of lithium chloride as a potential radioprotective agent on radiation response of DNA synthesis in mouse germinal cells. Radiat. Environ. Biophys., 1997, 36(2), 125-128.
[http://dx.doi.org/10.1007/s004110050063] [PMID: 9271800]
[52]
Yang, E.S.; Wang, H.; Jiang, G.; Nowsheen, S.; Fu, A.; Hallahan, D.E.; Xia, F. Lithium-mediated protection of hippocampal cells involves enhancement of DNA-PK-dependent repair in mice. J. Clin. Invest., 2009, 119(5), 1124-1135.
[http://dx.doi.org/10.1172/JCI34051] [PMID: 19425167]
[53]
Yang, Y.; Wu, N.; Tian, S.; Li, F.; Hu, H.; Chen, P.; Cai, X.; Xu, L.; Zhang, J.; Chen, Z.; Ge, J.; Yu, K.; Zhuang, J. Lithium promotes DNA stability and survival of ischemic retinal neurocytes by upregulating DNA ligase IV. Cell Death Dis., 2016, 7(11)e2473
[http://dx.doi.org/10.1038/cddis.2016.341] [PMID: 27853172]
[54]
Rouhani, M.; Goliaei, B.; Khodagholi, F.; Nikoofar, A. Lithium increases radiosensitivity by abrogating DNA repair in breast cancer spheroid culture. Arch. Iran Med., 2014, 17(5), 352-360.
[PMID: 24784865]
[55]
Watcharasit, P.; Bijur, G.N.; Song, L.; Zhu, J.; Chen, X.; Jope, R.S. Glycogen synthase kinase-3beta (GSK3beta) binds to and promotes the actions of p53. J. Biol. Chem., 2003, 278(49), 48872-48879.
[http://dx.doi.org/10.1074/jbc.M305870200] [PMID: 14523002]
[56]
Wang, D.; Gao, L.; Liu, X.; Yuan, C.; Wang, G. Improved antitumor effect of ionizing radiation in combination with rapamycin for treating nasopharyngeal carcinoma. Oncol. Lett., 2017, 14(1), 1105-1108.
[http://dx.doi.org/10.3892/ol.2017.6208] [PMID: 28693280]
[57]
Ren, J.; Liu, T.; Han, Y.; Wang, Q.; Chen, Y.; Li, G.; Jiang, L. GSK-3β inhibits autophagy and enhances radiosensitivity in non-small cell lung cancer. Diagn. Pathol., 2018, 13(1), 33.
[http://dx.doi.org/10.1186/s13000-018-0708-x] [PMID: 29793508]
[58]
Shimura, T.; Kakuda, S.; Ochiai, Y.; Kuwahara, Y.; Takai, Y.; Fukumoto, M. Targeting the AKT/GSK3β/cyclin D1/Cdk4 survival signaling pathway for eradication of tumor radioresistance acquired by fractionated radiotherapy. Int. J. Radiat. Oncol. Biol. Phys., 2011, 80(2), 540-548.
[http://dx.doi.org/10.1016/j.ijrobp.2010.12.065] [PMID: 21398050]
[59]
Xiao, S.; Yang, Z.; Lv, R.; Zhao, J.; Wu, M.; Liao, Y.; Liu, Q. miR-135b contributes to the radioresistance by targeting GSK3β in human glioblastoma multiforme cells. PLoS One, 2014, 9(9)e108810
[http://dx.doi.org/10.1371/journal.pone.0108810] [PMID: 25265336]

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