Generic placeholder image

Current Radiopharmaceuticals

Editor-in-Chief

ISSN (Print): 1874-4710
ISSN (Online): 1874-4729

Research Article

Comparative Study of Extremely Low-Frequency Electromagnetic Field, Radiation, and Temozolomide Administration in Spheroid and Monolayer Forms of the Glioblastoma Cell Line (T98)

Author(s): Rasoul Yahyapour, Samideh Khoei*, Zeinab Kordestani, Mohammad Hasan Larizadeh, Ali Jomehzadeh, Maryam Amirinejad and Meysam Ahmadi-Zeidabadi*

Volume 16, Issue 2, 2023

Published on: 26 December, 2022

Page: [123 - 132] Pages: 10

DOI: 10.2174/1874471016666221207163043

Price: $65

Abstract

Background: Glioblastoma is the most common primary malignant tumor of the central nervous system. The patient's median survival rate is 13.5 months, so it is necessary to explore new therapeutic approaches.

Objective: Extremely low-frequency electromagnetic field (EMF) has been explored as a noninvasive cancer treatment. This study applied the EMF with previous conventional chemoradiotherapy for glioblastoma.

Methods: In this study, we evaluated the cytotoxic effects of EMF (50 Hz, 100 G), temozolomide (TMZ), and radiation (Rad) on gene expression of T98 glioma cell lines in monolayer and spheroid cell cultures.

Results: Treatment with Rad and EMF significantly increased apoptosis-related gene expression compared to the control group in monolayers and spheroids (p<0.001). The expression of apoptotic-related genes in monolayers was higher than the similar spheroid groups (p<0.001). We found that treatment with TMZ and EMF could increase the gene expression of the autophagy cascade markers compared to the control group (p<0.001). Autophagy-related gene expression in spheroids was higher than in the similar monolayer group (p<0.001). We demonstrated that coadministration of EMF, TMZ, and Rad significantly reduced cell cycle and drug resistance gene expression in monolayers and spheroids (p<0.001) compared to the control group.

Conclusion: The combinational use of TMZ, Rad and, EMF showed the highest antitumor activity by inducing apoptosis and autophagy signaling pathways and inhibiting cell cycle and drug resistance gene expression. Furthermore, EMF increased TMZ or radiation efficiency.

Graphical Abstract

[1]
Li, K.; Lu, D.; Guo, Y.; Wang, C.; Liu, X.; Liu, Y.; Liu, D. Trends and patterns of incidence of diffuse glioma in adults in the United States, 1973-2014. Cancer Med., 2018, 7(10), 5281-5290.
[http://dx.doi.org/10.1002/cam4.1757] [PMID: 30175510]
[2]
Alexander, B.M.; Cloughesy, T.F. Adult Glioblastoma. J. Clin. Oncol., 2017, 35(21), 2402-2409.
[http://dx.doi.org/10.1200/JCO.2017.73.0119] [PMID: 28640706]
[3]
Marenco-Hillembrand, L.; Wijesekera, O.; Suarez-Meade, P.; Mampre, D.; Jackson, C.; Peterson, J.; Trifiletti, D.; Hammack, J.; Ortiz, K.; Lesser, E. Trends in glioblastoma: Outcomes over time and type of intervention: A systematic evidence based analysis. J. Neurooncol., 2020, 147(2), 297-307.
[http://dx.doi.org/10.1007/s11060-020-03451-6]
[4]
Tykocki, T.; Eltayeb, M. Ten-year survival in glioblastoma. A systematic review. J. Clin. Neurosci., 2018, 54, 7-13.
[http://dx.doi.org/10.1016/j.jocn.2018.05.002] [PMID: 29801989]
[5]
Poh, P.S.P.; Seeliger, C.; Unger, M.; Falldorf, K.; Balmayor, E.R.; van Griensven, M. Osteogenic effect and cell signaling activation of extremely low-frequency pulsed electromagnetic fields in adipose-derived mesenchymal stromal cells. Stem Cells Int., 2018, 2018, 1-11.
[http://dx.doi.org/10.1155/2018/5402853] [PMID: 30123287]
[6]
Miyakoshi, J. Biological responses to extremely low-frequency electromagnetic fields. J. Dermatol. Science. Suppl., 2006, 2(1), S23-S30.
[http://dx.doi.org/10.1016/j.descs.2006.08.003]
[7]
Destefanis, M.; Viano, M.; Leo, C.; Gervino, G.; Ponzetto, A.; Silvagno, F. Extremely low frequency electromagnetic fields affect proliferation and mitochondrial activity of human cancer cell lines. Int. J. Radiat. Biol., 2015, 91(12), 964-972.
[http://dx.doi.org/10.3109/09553002.2015.1101648] [PMID: 26762464]
[8]
Dehghani-Soltani, S.; Eftekhar-Vaghefi, S.H.; Babaee, A.; Basiri, M.; Mohammadipoor-ghasemabad, L.; Vosough, P.; Ahmadi-Zeidabadi, M. Pulsed and discontinuous electromagnetic field exposure decreases temozolomide resistance in glioblastoma by modulating the expression of O6-methylguanine-DNA methyltransferase, cyclin-D1, and p53. Cancer Biother. Radiopharm., 2021, 36(7), 579-587.
[http://dx.doi.org/10.1089/cbr.2020.3851] [PMID: 32644826]
[9]
Akbarnejad, Z.; Eskandary, H.; Vergallo, C.; Nematollahi-Mahani, S.N.; Dini, L.; Darvishzadeh-Mahani, F.; Ahmadi, M. Effects of extremely low-frequency pulsed electromagnetic fields (ELF-PEMFs) on glioblastoma cells (U87). Electromagn. Biol. Med., 2017, 36(3), 238-247.
[http://dx.doi.org/10.1080/15368378.2016.1251452] [PMID: 27874284]
[10]
Baharara, J.; Hosseini, N.; Farzin, T.R. Extremely low frequency electromagnetic field sensitizes cisplatin-resistant human ovarian adenocarcinoma cells via P53 activation. Cytotechnology, 2016, 68(4), 1403-1413.
[http://dx.doi.org/10.1007/s10616-015-9900-y] [PMID: 26370097]
[11]
Katifelis, H.; Lyberopoulou, A.; Mukha, I.; Vityuk, N.; Grodzyuk, G.; Theodoropoulos, G.E.; Efstathopoulos, E.P.; Gazouli, M. Ag/Au bimetallic nanoparticles induce apoptosis in human cancer cell lines via P53, CASPASE-3 and BAX/BCL-2 pathways. Artif Cells Nanomed. Biotechnol., 2018, 46(sup3), S389-S398.
[http://dx.doi.org/10.1080/21691401.2018.1495645]
[12]
Ebadollahi, S.H.; Pouramir, M.; Zabihi, E.; Golpour, M.; Aghajanpour-Mir, M. The effect of arbutin on the expression of tumor suppressor P53, BAX/BCL-2 ratio and oxidative stress induced by tert-butyl hydroperoxide in fibroblast and LNcap cell lines. Cell J., 2021, 22(4), 532-541.
[http://dx.doi.org/10.22074/cellj.2021.6902] [PMID: 32347047]
[13]
Wu, P.; Zhao, J.; Guo, Y.; Yu, Y.; Wu, X.; Xiao, H. Ursodeoxycholic acid alleviates nonalcoholic fatty liver disease by inhibiting apoptosis and improving autophagy via activating AMPK. Biochem. Biophys. Res. Commun., 2020, 529(3), 834-838.
[http://dx.doi.org/10.1016/j.bbrc.2020.05.128] [PMID: 32595039]
[14]
Russo, A.; Cardile, V.; Graziano, A.; Avola, R.; Bruno, M.; Rigano, D. Involvement of Bax and Bcl-2 in induction of apoptosis by essential oils of three Lebanese Salvia species in human prostate cancer cells. Int. J. Mol. Sci., 2018, 19(1), 292.
[http://dx.doi.org/10.3390/ijms19010292] [PMID: 29351194]
[15]
Jung, S.; Jeong, H.; Yu, S.W. Autophagy as a decisive process for cell death. Exp. Mol. Med., 2020, 52(6), 921-930.
[http://dx.doi.org/10.1038/s12276-020-0455-4] [PMID: 32591647]
[16]
Mrakovcic, M.; Fröhlich, L. p53-mediated molecular control of autophagy in tumor cells. Biomolecules, 2018, 8(2), 14.
[http://dx.doi.org/10.3390/biom8020014] [PMID: 29561758]
[17]
Zhu, J.; Cai, Y.; Xu, K.; Ren, X.; Sun, J.; Lu, S.; Chen, J.; Xu, P. Beclin1 overexpression suppresses tumor cell proliferation and survival via an autophagy dependent pathway in human synovial sarcoma cells. Oncol. Rep., 2018, 40(4), 1927-1936.
[http://dx.doi.org/10.3892/or.2018.6599] [PMID: 30066884]
[18]
Alhoshani, A.; Alatawi, F.O.; Al-Anazi, F.E.; Attafi, I.M.; Zeidan, A.; Agouni, A.; El Gamal, H.M.; Shamoon, L.S.; Khalaf, S.; Korashy, H.M. BCL-2 inhibitor venetoclax induces autophagy-associated cell death, cell cycle arrest, and apoptosis in human breast cancer cells. OncoTargets Ther., 2020, 13, 13357-13370.
[http://dx.doi.org/10.2147/OTT.S281519] [PMID: 33414642]
[19]
Chen, Y.; Zhang, W.; Guo, X.; Ren, J.; Gao, A. The crosstalk between autophagy and apoptosis was mediated by phosphorylation of Bcl-2 and beclin1 in benzene-induced hematotoxicity. Cell Death Dis., 2019, 10(10), 772.
[http://dx.doi.org/10.1038/s41419-019-2004-4] [PMID: 31601785]
[20]
E. Hermosilla, V.; Salgado, G.; Riffo; Escobar, D.; Hepp, M.I.; Farkas, C.; Galindo, M.; Morín, V.; García-Robles, M.A.; Castro, A.F.; Pincheira, R. SALL2 represses cyclins D1 and E1 expression and restrains G1/S cell cycle transition and cancer-related phenotypes. Mol. Oncol., 2018, 12(7), 1026-1046.
[http://dx.doi.org/10.1002/1878-0261.12308] [PMID: 29689621]
[21]
Yu, W.; Zhang, L.; Wei, Q.; Shao, A. O6-methylguanine-DNA methyltransferase (MGMT): Challenges and new opportunities in glioma chemotherapy. Front. Oncol., 2020, 9, 1547.
[http://dx.doi.org/10.3389/fonc.2019.01547] [PMID: 32010632]
[22]
Chaicharoenaudomrung, N.; Kunhorm, P.; Noisa, P. Three-dimensional cell culture systems as an in vitro platform for cancer and stem cell modeling. World J. Stem Cells, 2019, 11(12), 1065-1083.
[http://dx.doi.org/10.4252/wjsc.v11.i12.1065] [PMID: 31875869]
[23]
Pinto, B.; Henriques, A.C.; Silva, P.M.A.; Bousbaa, H. Three-dimensional spheroids as in vitro preclinical models for cancer research. Pharmaceutics, 2020, 12(12), 1186.
[http://dx.doi.org/10.3390/pharmaceutics12121186] [PMID: 33291351]
[24]
Kordestani, Z.; Shahrokhi-Farjah, M.; Yazdi Rouholamini, S.E.; Saberi, A. Reduced ikk/nf-kb expression by Nigella sativa extract in breast cancer. Middle East J. Cancer, 2020, 11(2), 150-158.
[http://dx.doi.org/10.30476/mejc.2019.82140.1059]
[25]
Gunti, S.; Hoke, A.T.; Vu, K.P.; London, Jr. NR Organoid and spheroid tumor models: Techniques and applications. Cancers , 2021, 13(4), 874.
[26]
Białkowska, K.; Komorowski, P.; Bryszewska, M.; Miłowska, K. Spheroids as a type of three-dimensional cell cultures-examples of methods of preparation and the most important application. Int. J. Mol. Sci., 2020, 21(17), 6225.
[http://dx.doi.org/10.3390/ijms21176225] [PMID: 32872135]
[27]
Zhang, H.; Wang, R.; Yu, Y.; Liu, J.; Luo, T.; Fan, F. Glioblastoma treatment modalities besides surgery. J. Cancer, 2019, 10(20), 4793-4806.
[http://dx.doi.org/10.7150/jca.32475] [PMID: 31598150]
[28]
Karachi, A.; Dastmalchi, F.; Mitchell, D.A.; Rahman, M. Temozolomide for immunomodulation in the treatment of glioblastoma. Neuro-oncol., 2018, 20(12), 1566-1572.
[http://dx.doi.org/10.1093/neuonc/noy072] [PMID: 29733389]
[29]
Han, C.; Wang, S.; Wang, H.; Zhang, J. Exosomal Circ-HIPK3 facilitates tumor progression and temozolomide resistance by regulating miR-421/ZIC5 axis in glioma. Cancer Biother. Radiopharm., 2021, 36(7), 537-548.
[http://dx.doi.org/10.1089/cbr.2019.3492] [PMID: 32644821]
[30]
Wang, D.; Wang, Z.; Dai, X.; Zhang, L.; Li, M. Apigenin and temozolomide synergistically inhibit glioma growth through the PI3K/AKT Pathway. Cancer Biother. Radiopharm.,, 2021. cbr.2020.4283.
[http://dx.doi.org/10.1089/cbr.2020.4283] [PMID: 33471569]
[31]
Siller, S.; Lauseker, M.; Karschnia, P.; Niyazi, M.; Eigenbrod, S.; Giese, A.; Tonn, J.C. The number of methylated CpG sites within the MGMT promoter region linearly correlates with outcome in glioblastoma receiving alkylating agents. Acta Neuropathol. Commun., 2021, 9(1), 35.
[http://dx.doi.org/10.1186/s40478-021-01134-5] [PMID: 33663593]
[32]
Friedman, H.S.; Kerby, T.; Calvert, H. Temozolomide and treatment of malignant glioma. Clin. Cancer Res., 2000, 6(7), 2585-2597.
[http://dx.doi.org/10.1080/15368378.2019.1625784] [PMID: 10914698]
[33]
Ahmadi-Zeidabadi, M.; Akbarnejad, Z.; Esmaeeli, M.; Masoumi-Ardakani, Y.; Mohammadipoor-Ghasemabad, L.; Eskandary, H. Impact of extremely low-frequency electromagnetic field (100 Hz, 100 G) exposure on human glioblastoma U87 cells during Temozolomide administration. Electromagn. Biol. Med., 2019, 38(3), 198-209.
[http://dx.doi.org/10.1080/15368378.2019.1625784] [PMID: 31179753]
[34]
Alao, J.P. The regulation of cyclin D1 degradation: Roles in cancer development and the potential for therapeutic invention. Mol. Cancer, 2007, 6(1), 24.
[http://dx.doi.org/10.1186/1476-4598-6-24] [PMID: 17407548]
[35]
Sanjari, M.; Kordestani, Z.; Safavi, M.; Mashrouteh, M. FekriSoofi-Abadi, M.; Ghaseminejad Tafreshi., A. Enhanced expression of Cyclin D1and C-myc, a prognostic factor and possible mechanism for recurrenceof papillary thyroid carcinoma. Sci. Rep., 2020, 10, 5100.
[http://dx.doi.org/10.1038/s41598-020-61985-1] [PMID: 32198408]
[36]
Han, Q.; Chen, R.; Wang, F.; Chen, S.; Sun, X.; Guan, X.; Yang, Y.; Peng, B.; Pan, X.; Li, J.; Yi, W.; Li, P.; Zhang, H.; Feng, D.; Chen, A.; Li, X.; Li, S.; Yin, Z. Pre-exposure to 50 Hz-electromagnetic fields enhanced the antiproliferative efficacy of 5-fluorouracil in breast cancer MCF-7 cells. PLoS One, 2018, 13(4), e0192888.
[http://dx.doi.org/10.1371/journal.pone.0192888] [PMID: 29617363]
[37]
Aalami Zavareh, F.; Abdi, S.; Entezari, M. Up-regulation of miR-144 and miR-375 in the human gastric cancer cell line following the exposure to extremely low-frequency electromagnetic fields. Int. J. Radiat. Biol., 2021, 97(9), 1324-1332.
[http://dx.doi.org/10.1080/09553002.2021.1941376] [PMID: 34125651]
[38]
Carneiro, B.A.; El-Deiry, W.S. Targeting apoptosis in cancer therapy. Nat. Rev. Clin. Oncol., 2020, 17(7), 395-417.
[http://dx.doi.org/10.1038/s41571-020-0341-y] [PMID: 32203277]
[39]
Bold, R.J.; Termuhlen, P.M.; McConkey, D.J. Apoptosis, cancer and cancer therapy. Surg. Oncol., 1997, 6(3), 133-142.
[http://dx.doi.org/10.1016/S0960-7404(97)00015-7] [PMID: 9576629]
[40]
Lv, L.; Zhou, M.; Zhang, J.; Liu, F.; Qi, L.; Zhang, S.; Bi, Y.; Yu, Y. SOX6 suppresses the development of lung adenocarcinoma by regulating expression of p53, p21 CIPI, cyclin D1 and β‐catenin. FEBS Open Bio, 2020, 10(1), 135-146.
[http://dx.doi.org/10.1002/2211-5463.12762] [PMID: 31729835]
[41]
Huang, Z.; Yu, P.; Tang, J. Characterization of triple-negative breast cancer MDA-MB-231 cell spheroid model. OncoTargets Ther., 2020, 13, 5395-5405.
[http://dx.doi.org/10.2147/OTT.S249756] [PMID: 32606757]
[42]
Mizushima, N. Autophagy: Process and function. Genes Dev., 2007, 21(22), 2861-2873.
[http://dx.doi.org/10.1101/gad.1599207] [PMID: 18006683]
[43]
Yun, C.; Lee, S. The Roles of Autophagy in Cancer. Int. J. Mol. Sci., 2018, 19(11), 3466.
[http://dx.doi.org/10.3390/ijms19113466]
[44]
Kim, E.H.; Jo, Y.; Sai, S.; Park, M.J.; Kim, J.Y.; Kim, J.S.; Lee, Y.J.; Cho, J.M.; Kwak, S.Y.; Baek, J.H.; Jeong, Y.K.; Song, J.Y.; Yoon, M.; Hwang, S.G. Tumor-treating fields induce autophagy by blocking the Akt2/miR29b axis in glioblastoma cells. Oncogene, 2019, 38(39), 6630-6646.
[http://dx.doi.org/10.1038/s41388-019-0882-7] [PMID: 31375748]
[45]
Manea, A.J.; Ray, S.K. Regulation of autophagy as a therapeutic option in glioblastoma. Apoptosis, 2021, 26(11-12), 574-599.
[http://dx.doi.org/10.1007/s10495-021-01691-z] [PMID: 34687375]
[46]
Mejlvang, J.; Olsvik, H.; Svenning, S.; Bruun, J.A.; Abudu, Y.P.; Larsen, K.B.; Brech, A.; Hansen, T.E.; Brenne, H.; Hansen, T.; Stenmark, H.; Johansen, T. Starvation induces rapid degradation of selective autophagy receptors by endosomal microautophagy. J. Cell Biol., 2018, 217(10), 3640-3655.
[http://dx.doi.org/10.1083/jcb.201711002] [PMID: 30018090]
[47]
Li, F.; Zhang, C.; Zhang, G. m6A RNA methylation controls proliferation of human glioma cells by influencing cell apoptosis. Cytogenet. Genome Res., 2019, 159(3), 119-125.
[http://dx.doi.org/10.1159/000499062] [PMID: 31639789]
[48]
Cheng, Y.; Xie, P. Ganoderic acid A holds promising cytotoxicity on human glioblastoma mediated by incurring apoptosis and autophagy and inactivating PI3K/AKT signaling pathway. J. Biochem. Mol. Toxicol., 2019, 33(11), e22392.
[http://dx.doi.org/10.1002/jbt.22392] [PMID: 31503386]
[49]
Park, K-R.; Jeong, Y.; Lee, J.; Kwon, I.K.; Yun, H-M. Anti-tumor effects of jaceosidin on apoptosis, autophagy, and necroptosis in human glioblastoma multiforme. Am. J. Cancer Res., 2021, 11(10), 4919-4930.
[http://dx.doi.org/10.1002/jbt.22392] [PMID: 34765300]
[50]
Guo, Z.; Guozhang, H.; Wang, H.; Li, Z.; Liu, N. Ampelopsin inhibits human glioma through inducing apoptosis and autophagy dependent on ROS generation and JNK pathway. Biomed. Pharmacother., 2019, 116, 108524.
[http://dx.doi.org/10.1016/j.biopha.2018.12.136] [PMID: 31108349]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy