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Current Bioactive Compounds

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ISSN (Print): 1573-4072
ISSN (Online): 1875-6646

Research Article

Radiosensitizing Effects of Lithium Ascorbate on Normal and Tumor Lymphoid Cells under X-ray Irradiation

Author(s): Maria Tretayakova, Konstantin Brazovskii, Mikhail Belousov, Anton Artamonov, Sergei Stuchebrov, Aleksey Gogolev, Maria Larkina, Evgeniya Sukhikh and Evgenii Plotnikov*

Volume 19, Issue 8, 2023

Published on: 22 May, 2023

Article ID: e030523216456 Pages: 7

DOI: 10.2174/1573407219666230503094421

Price: $65

Abstract

The study aimed to assess the radiosensitizing effect of lithium ascorbate on tumor cells.

Background: Cancer cells radioresistance is an important factor restraining the success of X-ray therapy. Radiosensitizing drugs make tumor cells more sensitive to ionizing radiation and improve the effectiveness of radiotherapy. Although many chemical substances can potentiate the cytotoxic effects of X-ray radiation, their clinical applications are limited due to possible adverse reactions. Recently, several approaches have been proposed to develop new radiosensitizers that are highly effective and feature low toxicity. Among new enhancers of X-ray therapy, ascorbic acid, and its derivates demonstrate very low toxicity along with a wide therapeutic range. Lithium ascorbate is a promising X-ray therapy enhancer, but its mechanism of action is unknown. This research focuses on the radiosensitizing properties of lithium ascorbate and its effects on both tumor and normal irradiated cells.

Methods: The viability of the radiosensitized cells was evaluated by fluorescence flow cytometry using Annexin V-FITC Apoptosis Detection Kit and Cellular ROS Assay Kit (Abcam, UK). The test cell cultures included normal human mononuclear and Jurkat cells.

Results: Lithium ascorbate sensitizes normal human mononuclear and Jurkat cells towards ionizing radiation. The combined cytotoxic effect of X-ray irradiation (3 Gy) and lithium ascorbate (1,2 mmol/L) substantially exceeds the effects of the individual factors, i.e., synergetic action appears. The major types of cell death were late apoptosis and necrosis caused by excessive production of reactive oxygen species.

Conclusion: Lithium ascorbate in combination with X-ray irradiation exhibited the cytotoxic effect on both normal and cancer lymphoid cells by activating reactive oxygen species (ROS)-induced apoptosis. These findings indicate that lithium ascorbate is a promising substance to develop a new radiosensitizing drug.

Graphical Abstract

[1]
Olivares-Urbano, M.A.; Griñán-Lisón, C.; Marchal, J.A.; Núñez, M.I. CSC Radioresistance: A therapeutic challenge to improve radiotherapy effectiveness in cancer. Cells, 2020, 9(7), 1651.
[http://dx.doi.org/10.3390/cells9071651] [PMID: 32660072]
[2]
Kouvaris, J.R.; Kouloulias, V.E.; Vlahos, L.J. Amifostine: The first selective-target and broad-spectrum radioprotector. Oncologist, 2007, 12(6), 738-747.
[http://dx.doi.org/10.1634/theoncologist.12-6-738] [PMID: 17602063]
[3]
Arbiser, J.L.; Bonner, M.Y.; Gilbert, L.C. Targeting the duality of cancer. NPJ Precis. Oncol., 2017, 1(1), 23.
[http://dx.doi.org/10.1038/s41698-017-0026-x] [PMID: 28825045]
[4]
Gong, L.; Zhang, Y.; Liu, C.; Zhang, M.; Han, S. Application of radiosensitizers in cancer radiotherapy. Int. J. Nanomed., 2021, 16, 1083-1102.
[http://dx.doi.org/10.2147/IJN.S290438] [PMID: 33603370]
[5]
Plotnikov, E.; Korotkova, E.; Voronova, O. Lithium salts of Krebs cycle substrates as potential normothymic antioxidant agents. J. Pharm. Bioallied Sci., 2018, 10(4), 240-245.
[http://dx.doi.org/10.4103/JPBS.JPBS_140_18] [PMID: 30568382]
[6]
Tondo, L.; Alda, M.; Bauer, M.; Bergink, V.; Grof, P.; Hajek, T.; Lewitka, U.; Licht, R.W.; Manchia, M.; Müller-Oerlinghausen, B.; Nielsen, R.E.; Selo, M.; Simhandl, C.; Baldessarini, R.J. Clinical use of lithium salts: Guide for users and prescribers. Int. J. Bipolar Disord., 2019, 7(1), 16.
[http://dx.doi.org/10.1186/s40345-019-0151-2] [PMID: 31328245]
[7]
Duffy, D.J.; Krstic, A.; Schwarzl, T.; Higgins, D.G.; Kolch, W. GSK3 inhibitors regulate MYCN mRNA levels and reduce neuroblastoma cell viability through multiple mechanisms, including p53 and Wnt signaling. Mol. Cancer Ther., 2014, 13(2), 454-467.
[http://dx.doi.org/10.1158/1535-7163.MCT-13-0560-T] [PMID: 24282277]
[8]
Zaidan, M.; Stucker, F.; Stengel, B.; Vasiliu, V.; Hummel, A.; Landais, P.; Boffa, J.J.; Ronco, P.; Grünfeld, J.P.; Servais, A. Increased risk of solid renal tumors in lithium-treated patients. Kidney Int., 2014, 86(1), 184-190.
[http://dx.doi.org/10.1038/ki.2014.2] [PMID: 24451323]
[9]
Pottegård, A.; Ennis, Z.N.; Hallas, J.; Jensen, B.L.; Madsen, K.; Friis, S. Long-term use of lithium and risk of colorectal adenocarcinoma: A nationwide case–control study. Br. J. Cancer, 2016, 114(5), 571-575.
[http://dx.doi.org/10.1038/bjc.2016.10] [PMID: 26867160]
[10]
Plotnikov, E.; Plotnikov, E.; Korotkova, E.; Voronova, O.; Dorozhko, E.; Bohan, N.; Plotnikov, S. Lithium-based antioxidants: Electrochemical properties and influence on immune cells. Physiol. Pharmacol, 2015, 19, 107-113.
[11]
Plotnikov, E.; Voronova, O.; Linert, W.; Martemianov, D.; Korotkova, E.; Dorozhko, E.; Astashkina, A.; Martemianova, I.; Ivanova, S.; Bokhan, N. Antioxidant and immunotropic properties of some lithium salts. J. Appl. Pharm. Sci., 2016, 6, 86-89.
[http://dx.doi.org/10.7324/JAPS.2016.600115]
[12]
Losenkov, I.S.; Plotnikov, E.V.; Epimakhova, E.V. Study of cytotoxic effect of lithium ascorbate and its influence on oxidative stress in vitro. Sib. Her. Psychiatry Addict. Psychiatry, 2018, 98, 24-29.
[http://dx.doi.org/10.26617/1810-3111-2018-1(98)-24-29]
[13]
Pauling, L.; Pauling, L.; Moertel, C. A proposition: Megadoses of vitamin C are valuable in the treatment of cancer. Nutr. Rev., 1986, 44(1), 28-29.
[http://dx.doi.org/10.1111/j.1753-4887.1986.tb07553.x] [PMID: 3951764]
[14]
Cameron, E.; Pauling, L. Supplemental ascorbate in the supportive treatment of cancer: Reevaluation of prolongation of survival times in terminal human cancer. Proc. Natl. Acad. Sci., 1978, 75(9), 4538-4542.
[http://dx.doi.org/10.1073/pnas.75.9.4538] [PMID: 279931]
[15]
Reczek, C.R.; Chandel, N.S. Revisiting vitamin C and cancer. Science, 2015, 350(6266), 1317-1318.
[http://dx.doi.org/10.1126/science.aad8671] [PMID: 26659042]
[16]
Blaszczak, W.; Barczak, W.; Masternak, J.; Kopczyński, P.; Zhitkovich, A.; Rubiś, B. Vitamin C as a modulator of the response to cancer therapy. Molecules, 2019, 24(3), 453.
[http://dx.doi.org/10.3390/molecules24030453] [PMID: 30695991]
[17]
Padayatty, S.J.; Levine, M.; Vitamin, C. Vitamin C: The known and the unknown and Goldilocks. Oral Dis., 2016, 22(6), 463-493.
[http://dx.doi.org/10.1111/odi.12446] [PMID: 26808119]
[18]
Zhao, H.; Zhuang, Y.; Li, R.; Liu, Y.; Mei, Z.; He, Z.; Zhou, F.; Zhou, Y. Effects of different doses of X-ray irradiation on cell apoptosis, cell cycle, DNA damage repair and glycolysis in HeLa cells. Oncol. Lett., 2018, 17(1), 42-54.
[http://dx.doi.org/10.3892/ol.2018.9566] [PMID: 30655736]
[19]
Frey, B.; Hehlgans, S.; Rödel, F.; Gaipl, U.S. Modulation of inflammation by low and high doses of ionizing radiation: Implications for benign and malign diseases. Cancer Lett., 2015, 368(2), 230-237.
[http://dx.doi.org/10.1016/j.canlet.2015.04.010] [PMID: 25888451]
[20]
Deubzer, B.; Mayer, F.; Kuçi, Z.; Niewisch, M.; Merkel, G.; Handgretinger, R.; Bruchelt, G. H(2O(2)-mediated cytotoxicity of pharmacologic ascorbate concentrations to neuroblastoma cells: Potential role of lactate and ferritin. Cell. Physiol. Biochem., 2010, 25(6), 767-774.
[http://dx.doi.org/10.1159/000315098] [PMID: 20511723]
[21]
Gibhardt, C.S.; Roth, B.; Schroeder, I.; Fuck, S.; Becker, P.; Jakob, B.; Fournier, C.; Moroni, A.; Thiel, G. X-ray irradiation activates K+ channels via H2O2 signaling. Sci. Rep., 2015, 5(1), 13861.
[http://dx.doi.org/10.1038/srep13861] [PMID: 26350345]
[22]
Shen, J.; Griffiths, P.T.; Campbell, S.J.; Utinger, B.; Kalberer, M.; Paulson, S.E. Ascorbate oxidation by iron, copper and reactive oxygen species: Review, model development, and derivation of key rate constants. Sci. Rep., 2021, 11(1), 7417.
[http://dx.doi.org/10.1038/s41598-021-86477-8] [PMID: 33795736]
[23]
Adwas, A.A.; Elsayed, A.S.I.; Azab, A.E. Oxidative stress and antioxidant mechanisms in human body. J. Appl. Biotechnol. Bioeng., 2019, 6(1), 43-47.
[http://dx.doi.org/10.1097/WOX.0b013e3182439613]
[24]
Pizzino, G.; Irrera, N.; Cucinotta, M.; Pallio, G.; Mannino, F.; Arcoraci, V.; Squadrito, F.; Altavilla, D.; Bitto, A. Oxidative stress: Harms and benefits for human health. Oxid. Med. Cell. Longev., 2017, 2017, 8416763.
[http://dx.doi.org/10.1155/2017/8416763] [PMID: 28819546]
[25]
Hong, J.M.; Kim, J.H.; Kang, J.S.; Lee, W.J.; Hwang, Y.; il Vitamin, C. Vitamin C is taken up by human T cells via sodium-dependent vitamin C transporter 2 (SVCT2 ) and exerts inhibitory effects on the activation of these cells in vitro. Anat. Cell Biol., 2016, 49(2), 88-98.
[http://dx.doi.org/10.5115/acb.2016.49.2.88] [PMID: 27382510]
[26]
Yanagita, T.; Maruta, T.; Uezono, Y.; Satoh, S.; Yoshikawa, N.; Nemoto, T.; Kobayashi, H.; Wada, A. Lithium inhibits function of voltage-dependent sodium channels and catecholamine secretion independent of glycogen synthase kinase-3 in adrenal chromaffin cells. Neuropharmacology, 2007, 53(7), 881-889.
[http://dx.doi.org/10.1016/j.neuropharm.2007.08.018] [PMID: 17950380]

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