https://doi.org/10.4081/ejh.2024.4106
Low ozone concentrations do not exert cytoprotective effects on tamoxifen-treated breast cancer cells in vitro
Submitted: 11 July 2024
Accepted: 2 September 2024
Published: 9 September 2024
Accepted: 2 September 2024
Abstract Views: 414
PDF: 118
HTML: 0
HTML: 0
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Authors
Medical treatment with low ozone concentrations proved to exert therapeutic effects in various diseases by inducing a cytoprotective antioxidant response through the nuclear factor erythroid derived-like 2 (Nrf2) transcription factor pathway. Low ozone doses are increasingly administered to oncological patients as a complementary treatment to mitigate some adverse side-effects of antitumor treatments. However, a widespread concern exists about the possibility that the cytoprotective effect of Nrf2 activation may confer drug resistance to cancer cells or at least reduce the efficacy of antitumor agents. In this study, the effect of low ozone concentrations on tamoxifen-treated MCF7 human breast cancer cells has been investigated in vitro by histochemical and molecular techniques. Results demonstrated that cell viability, proliferation and migration were generally similar in tamoxifen-treated cells as in cells concomitantly treated with tamoxifen and ozone. Notably, low ozone concentrations were unable to overstimulate the antioxidant response through the Nfr2 pathway, thus excluding a possible ozone-driven cytoprotective effect that would lead to increased tumor cell survival during the antineoplastic treatment. These findings, though obtained in an in vitro model, support the hypothesis that low ozone concentrations do not interfere with the tamoxifen-induced effects on breast cancer cells.
Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998;90:1371-88.
DOI: https://doi.org/10.1093/jnci/90.18.1371
Li W, Shi X, Xu Y, Wan J, Wei S, Zhu R. Tamoxifen promotes apoptosis and inhibits invasion in estrogen-positive breast cancer MCF-7 cells. Mol Med Rep 2017;16:478-84.
DOI: https://doi.org/10.3892/mmr.2017.6603
Ahmed NS, Samec M, Liskova A, Kubatka P, Saso L. Tamoxifen and oxidative stress: an overlooked connection. Discov Oncol 2021;12:17.
DOI: https://doi.org/10.1007/s12672-021-00411-y
Re L, Mawsouf MN, Menéndez S, León OS, Sánchez GM, Hernández F. Ozone therapy: clinical and basic evidence of its therapeutic potential. Arch Med Res 2008;39:17-26.
DOI: https://doi.org/10.1016/j.arcmed.2007.07.005
Elvis AM, Ekta JS. Ozone therapy: A clinical review. J Nat Sci Biol Med 2011;2:66-70.
DOI: https://doi.org/10.4103/0976-9668.82319
Bocci V. How a calculated oxidative stress can yield multiple therapeutic effects. Free Radic Res 2012;46:1068-75.
DOI: https://doi.org/10.3109/10715762.2012.693609
Wang L, Chen H, Liu XH, Chen ZY, Weng XD, Qiu T, et al. Ozone oxidative preconditioning inhibits renal fibrosis induced by ischemia and reperfusion injury in rats. Exp Ther Med 2014;8:1764-8.
DOI: https://doi.org/10.3892/etm.2014.2004
Izadi M, Kheirjou R, Mohammadpour R, Aliyoldashi MH, Moghadam SJ, Khorvash F, et al. Efficacy of comprehensive ozone therapy in diabetic foot ulcer healing. Diabetes Metab Syndr 2019;13:822-5.
DOI: https://doi.org/10.1016/j.dsx.2018.11.060
Sen S, Sen S. Ozone therapy a new vista in dentistry: integrated review. Med Gas Res 2020;10:189-92.
DOI: https://doi.org/10.4103/2045-9912.304226
Scassellati C, Galoforo AC, Bonvicini C, Esposito C, Ricevuti G. Ozone: a natural bioactive molecule with antioxidant property as potential new strategy in aging and in neurodegenerative disorders. Ageing Res Rev 2020;63:101138.
DOI: https://doi.org/10.1016/j.arr.2020.101138
Niki E. Oxidative stress and antioxidants: Distress or eustress? Arch Biochem Biophys 2016;595:19-24.
DOI: https://doi.org/10.1016/j.abb.2015.11.017
Bocci V, Valacchi G. Nrf2 activation as target to implement therapeutic treatments. Front Chem 2015;3:4.
DOI: https://doi.org/10.3389/fchem.2015.00004
Galiè M, Costanzo M, Nodari A, Boschi F, Calderan L, Mannucci S, et al. Mild ozonisation activates antioxidant cell response by the Keap1/Nrf2 dependent pathway. Free Radic Biol Med 2018;124:114-21.
DOI: https://doi.org/10.1016/j.freeradbiomed.2018.05.093
Luongo M, Brigida AL, Mascolo L, Gaudino G. Possible therapeutic effects of ozone mixture on hypoxia in tumor development. Anticancer Res 2017;37:425-35.
DOI: https://doi.org/10.21873/anticanres.11334
Petrucci MT, Gallucci C, Agrillo A, Mustazza MC, Foà R. Role of ozone therapy in the treatment of osteonecrosis of the jaws in multiple myeloma patients. Haematologica 2007;92:1289-90.
DOI: https://doi.org/10.3324/haematol.11096
Clavo B, Santana-Rodriguez N, Llontop P, Gutierrez D, Ceballos D, Méndez C, et al. Ozone therapy in the management of persistent radiation-induced rectal bleeding in prostate cancer patients. Evid Based Complement Alternat Med 2015;2015:480369.
DOI: https://doi.org/10.1155/2015/480369
Kang KA, Hyun JW. Oxidative stress, Nrf2, and epigenetic modification contribute to anticancer drug resistance. Toxicol Res 2017;33:1-5.
DOI: https://doi.org/10.5487/TR.2017.33.1.001
Sweet F, Kao MS, Lee SC, Hagar WL, Sweet WE. Ozone selectively inhibits growth of human cancer cells. Science 1980;209:931-3.
DOI: https://doi.org/10.1126/science.7403859
Cannizzaro A, Verga Falzacappa CV, Martinelli M, Misiti S, Brunetti E, Bucci B. O(2/3) exposure inhibits cell progression affecting cyclin B1/cdk1 activity in SK-N-SH while induces apoptosis in SK-N-DZ neuroblastoma cells. J Cell Physiol 2007;213:115-25.
DOI: https://doi.org/10.1002/jcp.21097
Tirelli U, Cirrito C, Pavanello M, Del Pup L, Lleshi A, Berretta M. Oxygen-ozone therapy as support and palliative therapy in 50 cancer patients with fatigue - A short report. Eur Rev Med Pharmacol Sci 2018;22:8030-3.
DOI: https://doi.org/10.31021/ijii.20181101
Horwitz KB, Costlow ME, McGuire WL. MCF-7; a human breast cancer cell line with estrogen, androgen, progesterone, and glucocorticoid receptors. Steroids 1975;26:785-95.
DOI: https://doi.org/10.1016/0039-128X(75)90110-5
Costanzo M, Cisterna B, Vella A, Cestari T, Covi V, Tabaracci G, et al. Low ozone concentrations stimulate cytoskeletal organization, mitochondrial activity and nuclear transcription. Eur J Histochem 2015;59:2515.
DOI: https://doi.org/10.4081/ejh.2015.2515
Cisterna B, Costanzo M, Nodari A, Galiè M, Zanzoni S, Bernardi P, et al. Ozone activates the Nrf2 pathway and improves preservation of explanted adipose tissue in vitro. Antioxidants (Basel) 2020;9:989.
DOI: https://doi.org/10.3390/antiox9100989
Cappellozza E, Costanzo M, Calderan L, Galiè M, Angelini O, Tabaracci G, et al. Low ozone concentrations affect the structural and functional features of Jurkat T cells. Processes 2021;9:1030.
DOI: https://doi.org/10.3390/pr9061030
Lacavalla MA, Inguscio CR, Cisterna B, Bernardi P, Costanzo M, Galiè M, et al. Ozone at low concentration modulates microglial activity in vitro: a multimodal microscopy and biomolecular study. Microsc Res Tech 2022;85:3777-92.
DOI: https://doi.org/10.1002/jemt.24233
Cisterna B, Costanzo M, Lacavalla MA, Galiè M, Angelini O, Tabaracci G, et al. Low ozone concentrations differentially affect the structural and functional features of non-activated and activated fibroblasts in vitro. Int J Mol Sci 2021;22:10133.
DOI: https://doi.org/10.3390/ijms221810133
Inguscio CR, Dalla Pozza E, Dando I, Boschi F, Tabaracci G, Angelini O, et al. Mitochondrial features of mouse myoblasts are finely tuned by low doses of ozone: the evidence in vitro. Int J Mol Sci 2023;24:8900.
DOI: https://doi.org/10.3390/ijms24108900
Larini A, Bianchi L, Bocci V. The ozone tolerance: I) Enhancement of antioxidant enzymes is ozone dose-dependent in Jurkat cells. Free Radic Res 2003;37:1163-8.
DOI: https://doi.org/10.1080/10715760310001604170
Costanzo M, Cisterna B, Covi V, Tabaracci G, Malatesta M. An easy and inexpensive method to expose adhering cultured cells to ozonization. Microscopie 2015;23:46–52.
Shi R, Tang YQ, Miao H. Metabolism in tumor microenvironment: Implications for cancer immunotherapy. MedComm (2020) 2020;1:47-68.
DOI: https://doi.org/10.1002/mco2.6
de Visser KE, Joyce JA. The evolving tumor microenvironment: From cancer initiation to metastatic outgrowth. Cancer Cell 2023;41:374-403.
DOI: https://doi.org/10.1016/j.ccell.2023.02.016
Chen H, Tritton TR, Kenny N, Absher M, Chiu JF. Tamoxifen induces TGF-beta 1 activity and apoptosis of human MCF-7 breast cancer cells in vitro. J Cell Biochem 1996;61:9-17.
DOI: https://doi.org/10.1002/(SICI)1097-4644(19960401)61:1<9::AID-JCB2>3.3.CO;2-2
Budtz PE. Role of proliferation and apoptosis in net growth rates of human breast cancer cells (MCF-7) treated with oestradiol and/or tamoxifen. Cell Prolif 1999;32:289-302.
DOI: https://doi.org/10.1046/j.1365-2184.1999.3250289.x
Li Z, Carrier L, Belame A, Thiyagarajah A, Salvo VA, Burow ME, et al. Combination of methylselenocysteine with tamoxifen inhibits MCF-7 breast cancer xenografts in nude mice through elevated apoptosis and reduced angiogenesis. Breast Cancer Res Treat 2009;118:33-43.
DOI: https://doi.org/10.1007/s10549-008-0216-x
Danova M, Pellicciari C, Zibera C, Mangiarotti R, Gibelli N, Giordano M, et al. Cell cycle kinetic effects of tamoxifen on human breast cancer cells. Flow cytometric analyses of DNA content, BrdU labeling, Ki-67, PCNA, and statin expression. Ann N Y Acad Sci 1993;698:174-81.
DOI: https://doi.org/10.1111/j.1749-6632.1993.tb17206.x
Danova M, Pellicciari C, Bottone M, Gibelli N, Mangiarotti R, Zibera C, et al. Multiparametric assessment of the cell-cycle effects of tamoxifen on mcf-7 human breast-cancer cells. Oncol Rep 1994;1:739-45.
DOI: https://doi.org/10.3892/or.1.4.739
Tang S, Xu B, Li J, Zhong M, Hong Z, Zhao W, et al. Ozone induces BEL7402 cell apoptosis by increasing reactive oxygen species production and activating JNK. Ann Transl Med 2021;9:1257.
DOI: https://doi.org/10.21037/atm-21-3233
Han W, Chen S, Yuan W, Fan Q, Tian J, Wang X, et al. Oriented collagen fibers direct tumor cell intravasation. Proc Natl Acad Sci USA 2016;113:11208-13.
DOI: https://doi.org/10.1073/pnas.1610347113
Zbiral B, Weber A, Vivanco MD, Toca-Herrera JL. Characterization of breast cancer aggressiveness by cell mechanics. Int J Mol Sci 2023;24:12208.
DOI: https://doi.org/10.3390/ijms241512208
Metsiou DN, Siatis KE, Giannopoulou E, Papachristou DJ, Kalofonos HP, Koutras A, et al. The impact of anti-tumor agents on ER-positive MCF-7 and HER2-positive SKBR-3 breast cancer cells biomechanics. Ann Biomed Eng 2019;47:1711-24.
DOI: https://doi.org/10.1007/s10439-019-02284-3
Sakai J, Li J, Subramanian KK, Mondal S, Bajrami B, Hattori H, et al. Reactive oxygen species-induced actin glutathionylation controls actin dynamics in neutrophils. Immunity 2012;37:1037-49.
DOI: https://doi.org/10.1016/j.immuni.2012.08.017
Taulet N, Delorme-Walker VD, DerMardirossian C. Reactive oxygen species regulate protrusion efficiency by controlling actin dynamics. PLoS One 2012;7:e41342.
DOI: https://doi.org/10.1371/journal.pone.0041342
Muliyil S, Narasimha M. Mitochondrial ROS regulates cytoskeletal and mitochondrial remodeling to tune cell and tissue dynamics in a model for wound healing. Dev Cell 2014;28:239-52.
DOI: https://doi.org/10.1016/j.devcel.2013.12.019
Huang CH, Tang M, Shi C, Iglesias PA, Devreotes PN. An excitable signal integrator couples to an idling cytoskeletal oscillator to drive cell migration. Nat Cell Biol 2013;15:1307-16.
DOI: https://doi.org/10.1038/ncb2859
Gardel ML, Schneider IC, Aratyn-Schaus Y, Waterman CM. Mechanical integration of actin and adhesion dynamics in cell migration. Annu Rev Cell Dev Biol 2010;26:315-33.
DOI: https://doi.org/10.1146/annurev.cellbio.011209.122036
Verrazzo G, Coppola L, Luongo C, Sammartino A, Giunta R, Grassia A, et al. Hyperbaric oxygen, oxygen-ozone therapy, and rheologic parameters of blood in patients with peripheral occlusive arterial disease. Undersea Hyperb Med 1995;22:17-22.
Artis AS, Aydogan S, Sahin MG. The effects of colorectally insufflated oxygen-ozone on red blood cell rheology in rabbits. Clin Hemorheol Microcirc 2010;45:329-36.
DOI: https://doi.org/10.3233/CH-2010-1316
Scassellati C, Costanzo M, Cisterna B, Nodari A, Galiè M, Cattaneo A, et al. Effects of mild ozonisation on gene expression and nuclear domains organization in vitro. Toxicol In Vitro 2017;44:100-10.
DOI: https://doi.org/10.1016/j.tiv.2017.06.021
Loignon M, Miao W, Hu L, Bier A, Bismar TA, Scrivens PJ, et al. Cul3 overexpression depletes Nrf2 in breast cancer and is associated with sensitivity to carcinogens, to oxidative stress, and to chemotherapy. Mol Cancer Ther 2009;8:2432-40.
DOI: https://doi.org/10.1158/1535-7163.MCT-08-1186
Thangasamy A, Rogge J, Krishnegowda NK, Freeman JW, Ammanamanchi S. Novel function of transcription factor Nrf2 as an inhibitor of RON tyrosine kinase receptor-mediated cancer cell invasion. J Biol Chem 2011;286:32115-22.
DOI: https://doi.org/10.1074/jbc.M111.245746
Bekele RT, Venkatraman G, Liu RZ, Tang X, Mi S, Benesch MG, et al. Oxidative stress contributes to the tamoxifen-induced killing of breast cancer cells: implications for tamoxifen therapy and resistance. Sci Rep 2016;6:21164.
DOI: https://doi.org/10.1038/srep21164
Reinema FV, Sweep FCGJ, Adema GJ, Peeters WJM, Martens JWM, Bussink J, et al. Tamoxifen induces radioresistance through NRF2-mediated metabolic reprogramming in breast cancer. Cancer Metab 2023;11:3.
DOI: https://doi.org/10.1186/s40170-023-00304-4
Kim SK, Yang JW, Kim MR, Roh SH, Kim HG, Lee KY, et al. Increased expression of Nrf2/ARE-dependent anti-oxidant proteins in tamoxifen-resistant breast cancer cells. Free Radic Biol Med 2008;45:537-46.
DOI: https://doi.org/10.1016/j.freeradbiomed.2008.05.011
How to Cite
Inguscio, C. R., Carton, F., Cisterna, B., Rizzi, M., Boccafoschi, F., Tabaracci, G., & Malatesta, M. (2024). Low ozone concentrations do not exert cytoprotective effects on tamoxifen-treated breast cancer cells <i>in vitro</i>. European Journal of Histochemistry, 68(3). https://doi.org/10.4081/ejh.2024.4106
Copyright (c) 2024 The Author(s)
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
PAGEPress has chosen to apply the Creative Commons Attribution NonCommercial 4.0 International License (CC BY-NC 4.0) to all manuscripts to be published.
Similar Articles
- Claudia Frick, Hanna Luisa Martin, Johanna Bruder, Kerstin Lang, Heinz Breer, Topographic distribution pattern of morphologically different G cells in the murine antral mucosa , European Journal of Histochemistry: Vol. 61 No. 3 (2017)
- Azzurra Margiotta, Cinzia Progida, Oddmund Bakke, Cecilia Bucci, Characterization of the role of RILP in cell migration , European Journal of Histochemistry: Vol. 61 No. 2 (2017)
- A. Makowiecka, A. Simiczyjew, D. Nowak, A.J. Mazur, Varying effects of EGF, HGF and TGFβ on formation of invadopodia and invasiveness of melanoma cell lines of different origin , European Journal of Histochemistry: Vol. 60 No. 4 (2016)
- D. Nowak, A. J. Mazur, A. Popow-Woźniak, A. Radwańska, H. G. Mannherz, M. Malicka-Błaszkiewicz, Subcellular distribution and expression of cofilin and ezrin in human colon adenocarcinoma cell lines with different metastatic potential , European Journal of Histochemistry: Vol. 54 No. 2 (2010)
- Tadashi Yasui, Kenya Miyata, Chie Nakatsuka, Azuma Tsukise, Hiroshi Gomi, Morphological and histochemical characterization of the secretory epithelium in the canine lacrimal gland , European Journal of Histochemistry: Vol. 65 No. 4 (2021)
- Zhijiang Chen, Huili Wang, Bin Hu, Xinxin Chen, Meiyu Zheng, Lili Liang, Juanjuan Lyu, Qiyi Zeng, Transcription factor nuclear factor erythroid 2 p45-related factor 2 (NRF2) ameliorates sepsis-associated acute kidney injury by maintaining mitochondrial homeostasis and improving the mitochondrial function , European Journal of Histochemistry: Vol. 66 No. 3 (2022)
- Zhongzhu Tang, Lei Wang, Yunwang Chen, Xiaomin Zheng, Runyu Wang, Bingxue Liu, Shiqi Zhang, Huimin Wang, Quercetin reverses 5-fluorouracil resistance in colon cancer cells by modulating the NRF2/HO-1 pathway , European Journal of Histochemistry: Vol. 67 No. 3 (2023)
- Sabrina Giacoppo, Agnese Gugliandolo, Oriana Trubiani, Federica Pollastro, Gianpaolo Grassi, Placido Bramanti, Emanuela Mazzon, Cannabinoid CB2 receptors are involved in the protection of RAW264.7 macrophages against the oxidative stress: an in vitro study , European Journal of Histochemistry: Vol. 61 No. 1 (2017)
- A. Porzionato, M. Rucinski, V. Macchi, G. Sarasin, L.K. Malendowicz, R. De Caro, ECRG4 expression in normal rat tissues: expression study and literature review , European Journal of Histochemistry: Vol. 59 No. 2 (2015)
- J. Suchánková, S. Legartová, P. Sehnalová, S. Kozubek, S. Valente, D. Labella, A. Mai, C. Eckerich, F.O. Fackelmayer, D.V. Sorokin, E. Bartova, PRMT1 arginine methyltransferase accumulates in cytoplasmic bodies that respond to selective inhibition and DNA damage , European Journal of Histochemistry: Vol. 58 No. 2 (2014)
You may also start an advanced similarity search for this article.
Publication Facts
Metric
This article
Other articles
Peer reviewers
2
2.4
Reviewer profiles N/A
Author statements
Author statements
This article
Other articles
Data availability
N/A
16%
External funding
N/A
32%
Competing interests
N/A
11%
Metric
This journal
Other journals
Articles accepted
57%
33%
Days to publication
59
145
- Editor & editorial board
- profiles
- Academic society
- N/A
- Publisher
- PAGEPress Publications, Pavia, Italy
To learn about these publication facts, click 
PF is maintained by the Public Knowledge Project
