Apo-form of recombinant human lactoferrin changes the genome-wide DNA methylation level and the chromatin compaction degree in neuroblastoma cell line IMR-32

Abstract

BACKGROUND: Neuroblastoma is one of the most common extracranial solid tumors in childhood. At present, epigenetic disorders play a significant role in neoplasms development. Since epigenetic changes in the cell are quite dynamic and reversible, epigenome-modulating exogenous agents can be used in epigenetic targeted therapy for various types of tumors. Therefore, the identification of these agents is still significant. Lactoferrin is one such potential molecule from the transferrin family. Currently, the anti-tumor properties of lactoferrin have been identified, but its effect on the epigenome of cells of various tumors types, particularly on neuroblastomas, is practically unknown.

AIM: To study the effect of the exogenous recombinant human apolactoferrin on the viability and epigenomic status of IMR-32 neuroblastoma cells.

MATERIALS AND METHODS: We studied human IMR-32 neuroblastoma cells after 72 hours of exposure to 8 doses of recombinant human apolactoferrin: 0.1, 0.5, 1, 5, 10, 50, 100 and 500 µg/ml. The level of genome-wide DNA methylation and the degree of chromatin compaction in IMR-32 cells were quantified using commercial kits 5-mC DNA ELISA Kit, Global DNA Methylation – LINE-1 Kit, as well as enzymatic hydrolysis of MspI / HpaII and DNaseI.

RESULTS: The recombinant apolactoferrin reduces the viability of IMR-32 and, depending on the dose, differentially affects the level of genome-wide DNA methylation (СpG dinucleotides, CCGG sites, LINE-1 repeats) and the degree of chromatin compaction. At the same time, a complex picture of the epigenomic cellular response to the effect of apo-lactoferrin was observed (nonlinear nonmonotonic dose-effect relationship).

CONCLUSIONS: We assumed that apolactoferrin modulates gene activity through epigenetic mechanisms, in particular, by changing the DNA methylation pattern and affecting the chromatin structure, which may be one of the molecular mechanisms of its anti-tumor effect.

Keywords

apolactoferrin / neuroblastoma / IMR-32 / cell viability / epigenetic modifications / DNA methylation / chromatin compaction / MspI / HpaII / DNaseI / ELISA / ImageJ

References

[1] Stroganova AM, Karseladze AI. Neuroblastoma: morphological pattern, molecular genetic features, and prognostic factors. Advances in Molecular Oncology. 2016;3(1):32–43. (In Russ.) DOI: 10.17650/2313-805X.2016.3.1.32-43

[2] Строганова А.М., Карселадзе А.И. Нейробластома: морфологическая структура, молекулярно-генетические особенности и прогностические факторы // Успехи молекулярной онкологии. 2016. Т. 3, № 1. С. 32–43. DOI: 10.17650/2313-805X.2016.3.1.32-43

[3] Gómez S, Castellano G, Mayol G, et al. DNA methylation fingerprint of neuroblastoma reveals new biological and clinical insights. Genome Data. 2015;5:360–363. DOI: 10.1016/j.gdata.2015.07.016

[4] Gómez S., Castellano G., Mayol G. et al. DNA methylation fingerprint of neuroblastoma reveals new biological and clinical insights // Genome Data. 2015. Vol. 5. P. 360–363. DOI: 10.1016/j.gdata.2015.07.016

[5] Campos Cogo S, Gradowski Farias da Costa do Nascimento T, de Almeida Brehm Pinhatti F, et al. An overview of neuroblastoma cell lineage phenotypes and in vitro models. Exp Biol Med (Maywood). 2020;245(18):1637–1647. DOI: 10.1177/1535370220949237

[6] Campos Cogo S., Gradowski Farias da Costa do Nascimento T., de Almeida Brehm Pinhatti F. et al. An overview of neuroblastoma cell lineage phenotypes and in vitro models // Exp. Biol. Med. (Maywood). 2020. Vol. 245, No. 18. P. 1637–1647. DOI: 10.1177/1535370220949237

[7] Fetahu IS, Taschner-Mandl S. Neuroblastoma and the epigenome. Cancer Metastasis Rev. 2021;40(1):173–189. DOI: 10.1007/s10555-020-09946-y

[8] Fetahu I.S., Taschner-Mandl S. Neuroblastoma and the epigenome // Cancer Metastasis Rev. 2021. Vol. 40, No. 1. P. 173–189. DOI: 10.1007/s10555-020-09946-y

[9] Yang Q, Tian Y, Ostler KR, et al. Epigenetic alterations differ in phenotypically distinct human neuroblastoma cell lines. BMC Cancer. 2010;10:286. DOI: 10.1186/1471-2407-10-286

[10] Yang Q., Tian Y., Ostler K.R. et al. Epigenetic alterations differ in phenotypically distinct human neuroblastoma cell lines // BMC Cancer. 2010. Vol. 10. P. 286. DOI: 10.1186/1471-2407-10-286

[11] Jubierre L, Jiménez C, Rovira E, et al. Targeting of epigenetic regulators in neuroblastoma. Exp Mol Med. 2018;50(4):1–12. DOI: 10.1038/s12276-018-0077-2

[12] Jubierre L., Jiménez C., Rovira E. et al. Targeting of epigenetic regulators in neuroblastoma // Exp. Mol. Med. 2018. Vol. 50, No. 4. P. 1–12. DOI: 10.1038/s12276-018-0077-2

[13] Upton K, Modi A, Patel K, et al. Epigenomic profiling of neuroblastoma cell lines. Sci Data. 2020;7(1):116. DOI: 10.1038/s41597-020-0458-y

[14] Upton K., Modi A., Patel K. et al. Epigenomic profiling of neuroblastoma cell lines // Sci. Data. 2020. Vol. 7, No. 1. P. 116. DOI: 10.1038/s41597-020-0458-y

[15] Yáñez Y, Grau E, Rodríguez-Cortez VC, et al. Two independent epigenetic biomarkers predict survival in neuroblastoma. Clin Epigenetics. 2015;7(1):16. DOI: 10.1186/s13148-015-0054-8

[16] Yáñez Y., Grau E., Rodríguez-Cortez V.C. et al. Two independent epigenetic biomarkers predict survival in neuroblastoma // Clin. Epigenetics. 2015. Vol. 7, No. 1. P. 16. DOI: 10.1186/s13148-015-0054-8

[17] Olsson M, Beck S, Kogner P, et al. Genome-wide methylation profiling identifies novel methylated genes in neuroblastoma tumors. Epigenetics. 2016;11(1):74–84. DOI: 10.1080/15592294.2016.1138195

[18] Olsson M., Beck S., Kogner P. et al. Genome-wide methylation profiling identifies novel methylated genes in neuroblastoma tumors // Epigenetics. 2016. Vol. 11, No. 1. P. 74–84. DOI: 10.1080/15592294.2016.1138195

[19] Kiss NB, Kogner P, Johnsen JI, et al. Quantitative global and gene-specific promoter methylation in relation to biological properties of neuroblastomas. BMC Med Genet. 2012;13:83. DOI: 10.1186/1471-2350-13-83

[20] Kiss N.B., Kogner P., Johnsen J.I. et al. Quantitative global and gene-specific promoter methylation in relation to biological properties of neuroblastomas // BMC Med. Genet. 2012. Vol. 13. P. 83. DOI: 10.1186/1471-2350-13-83

[21] Gómez S, Castellano G, Mayol G, et al. DNA methylation fingerprint of neuroblastoma reveals new biological and clinical insights. Epigenomics. 2015;7(7):1137–1153. DOI: 10.2217/epi.15.49

[22] Gómez S., Castellano G., Mayol G. et al. DNA methylation fingerprint of neuroblastoma reveals new biological and clinical insights // Epigenomics. 2015. Vol. 7, No. 7. P. 1137–1153. DOI: 10.2217/epi.15.49

[23] Muotri AR, Marchetto MC, Coufal NG, et al. L1 retrotransposition in neurons is modulated by MeCP2. Nature. 2010;468(7322):443–446. DOI: 10.1038/nature09544

[24] Muotri A.R., Marchetto M.C., Coufal N.G. et al. L1 retrotransposition in neurons is modulated by MeCP2 // Nature. 2010. Vol. 468, No. 7322. P. 443–446. DOI: 10.1038/nature09544

[25] Giorgi G, Marcantonio P, Del Re B. LINE-1 retrotransposition in human neuroblastoma cells is affected by oxidative stress. Cell Tissue Res. 2011;346(3):383–391. DOI: 10.1007/s00441-011-1289-0

[26] Giorgi G., Marcantonio P., Del Re B. LINE-1 retrotransposition in human neuroblastoma cells is affected by oxidative stress // Cell Tissue Res. 2011. Vol. 346, No. 3. P. 383–391. DOI: 10.1007/s00441-011-1289-0

[27] Jönsson ME, Ludvik Brattås P, Gustafsson C, et al. Activation of neuronal genes via LINE-1 elements upon global DNA demethylation in human neural progenitors. Nat Commun. 2019;10(1):3182. DOI: 10.1038/s41467-019-11150-8

[28] Jönsson M.E., Ludvik Brattås P., Gustafsson C. et al. Activation of neuronal genes via LINE-1 elements upon global DNA demethylation in human neural progenitors // Nat. Commun. 2019. Vol. 10, No. 1. P. 3182. DOI: 10.1038/s41467-019-11150-8

[29] Dyachenko OV, Schevchuk TV, Kretzner L, et al. Human non-CG methylation: are human stem cells plant-like? Epigenetics. 2010;5(7):569–572. DOI: 10.4161/epi.5.7.12702

[30] Dyachenko O.V., Schevchuk T.V., Kretzner L. et al. Human non-CG methylation: are human stem cells plant-like? // Epigenetics. 2010. Vol. 5, No. 7. P. 569–572. DOI: 10.4161/epi.5.7.12702

[31] Whongsiri P, Pimratana C, Wijitsettakul U, et al. Oxidative stress and LINE-1 reactivation in bladder cancer are epigenetically linked through active chromatin formation. Free Radic Biol Med. 2019;134:419–428. DOI: 10.1016/j.freeradbiomed.2019.01.031

[32] Whongsiri P., Pimratana C., Wijitsettakul U. et al. Oxidative stress and LINE-1 reactivation in bladder cancer are epigenetically linked through active chromatin formation // Free Radic. Biol. Med. 2019. Vol. 134. P. 419–428. DOI: 10.1016/j.freeradbiomed.2019.01.031

[33] Ak T, Gülçin I. Antioxidant and radical scavenging properties of curcumin. Chem Biol Interact. 2008;174(1):27–37. 20080507. DOI: 10.1016/j.cbi.2008.05.003

[34] Ak T., Gülçin I. Antioxidant and radical scavenging properties of curcumin // Chem. Biol. Interact. 2008. Vol. 174, No. 1. P. 27–37. DOI: 10.1016/j.cbi.2008.05.003

[35] Zhai K, Brockmüller A, Kubatka P, et al. Curcumin’s beneficial effects on neuroblastoma: mechanisms, challenges, and potential solutions. Biomolecules. 2020;10(11):1469. DOI: 10.3390/biom10111469

[36] Zhai K., Brockmüller A., Kubatka P. Curcumin’s beneficial effects on neuroblastoma: Mechanisms, challenges, and potential solutions // Biomolecules. 2020. Vol. 10, No. 11. P. 1469. DOI: 10.3390/biom10111469

[37] Borzenkova NV, Balabushevich NG, Larionova NI. Lactoferrin: physical and chemical properties, biological functions, delivery systems, pharmaceutical and nutraceutical preparations (review). Biopharmaceutical Journal. 2010;2(3):3–19. (In Russ.)

[38] Борзенкова Н.В., Балабушевич Н.Г., Ларионова Н.И. Лактоферрин: физико-химические свойства, биологические функции, системы доставки, лекарственные препараты и биологически активные добавки (обзор) // Биофармацевтический журнал. 2010. Т. 2, № 3. С. 3–19.

[39] Hao L, Shan Q, Wei J, et al. Lactoferrin: Major physiological functions and applications. Curr Protein Pept Sci. 2019;20(2):139–144. DOI: 10.2174/1389203719666180514150921

[40] Hao L., Shan Q., Wei J. et al. Lactoferrin: major physiological functions and applications // Curr. Protein Pept. Sci. 2019. Vol. 20, No. 2. P. 139–144. DOI: 10.2174/1389203719666180514150921

[41] Aleshina G.M. Lactoferrin — an endogenous regulator of the protective functions of the organism. Medical Academic Journal. 2019;19(1):35–44. (In Russ.) DOI: 10.17816/MAJ19135-44

[42] Алешина Г.М. Лактоферрин — эндогенный регулятор защитных функций организма // Медицинский академический журнал. 2019. Т. 19, № 1. С. 35–44. DOI: 10.17816/MAJ19135-44

[43] Zakharova ET, Kostevich VA, Sokolov AV, Vasilyev VB. Human apo-lactoferrin as a physiological mimetic of hypoxia stabilizes hypoxia-inducible factor-1 alpha. Biometals. 2012;25(6):1247–1259. DOI: 10.1007/s10534-012-9586-y

[44] Zakharova E.T., Kostevich V.A., Sokolov A.V., Vasilyev V.B. Human apo-lactoferrin as a physiological mimetic of hypoxia stabilizes hypoxia-inducible factor-1 alpha // Biometals. 2012. Vol. 25, No. 6. P. 1247–1259. DOI: 10.1007/s10534-012-9586-y

[45] Sokolov AV, Dubrovskaya NM, Kostevich VA, et al. Lactoferrin induces erythropoietins and rescues cognitive functions in the offspring of rats subjected to prenatal hypoxia. Nutrients. 2022;14(7):1399. DOI: 10.3390/nu14071399

[46] Sokolov A.V., Dubrovskaya N.M., Kostevich V.A. et al. Lactoferrin Induces erythropoietin synthesis and rescues cognitive functions in the offspring of rats subjected to prenatal hypoxia // Nutrients. 2022. Vol. 14, No. 7. P. 1399. DOI: 10.3390/nu14071399

[47] Suzuki YA, Lopez V, Lönnerdal B. Mammalian lactoferrin receptors: structure and function. Cell Mol Life Sci. 2005;62(22):2560–2575. DOI: 10.1007/s00018-005-5371-1

[48] Suzuki Y.A., Lopez V., Lönnerdal B. Mammalian lactoferrin receptors: structure and function // Cell Mol. Life Sci. 2005. Vol. 62, No. 22. P. 2560–2575. DOI: 10.1007/s00018-005-5371-1

[49] Li YQ, Guo C. A review on lactoferrin and centraln system diseases. Cells. 2021;10(7):1810. DOI: 10.3390/cells10071810

[50] Li Y.Q., Guo C. A review on lactoferrin and central nervous system diseases // Cells. 2021. Vol. 10, No. 7. P. 1810. DOI: 10.3390/cells10071810

[51] García-Montoya IA, Cendón TS, Arévalo-Gallegos S, et al. Lactoferrin a multiple bioactive protein: an overview. Biochim Biophys Acta. 2012;1820(3):226–236. DOI: 10.1016/j.bbagen.2011.06.018

[52] García-Montoya I.A., Cendón T.S., Arévalo-Gallegos S., Rascón-Cruz Q. Lactoferrin a multiple bioactive protein: an overview // Biochim. Biophys. Acta. 2012. Vol. 1820, No. 3. P. 226–236. DOI: 10.1016/j.bbagen.2011.06.018

[53] Gibbons JA, Kanwar RK, Kanwar JR. Lactoferrin and cancer in different cancer models. Front Biosci (Schol Ed). 2011;3(3):1080–1088. DOI: 10.2741/212

[54] Gibbons J.A., Kanwar R.K., Kanwar J.R. Lactoferrin and cancer in different cancer models // Front. Biosci. (Schol Ed). 2011. Vol. 3, No. 3. P. 1080–1088. DOI: 10.2741/212

[55] Zhang Y, Lima CF, Rodrigues LR. Anticancer effects of lactoferrin: underlying mechanisms and future trends in cancer therapy. Nutr Rev. 2014;72(12):763–773. DOI: 10.1111/nure.12155

[56] Zhang Y., Lima C.F., Rodrigues L.R. Anticancer effects of lactoferrin: underlying mechanisms and future trends in cancer therapy // Nutr. Rev. 2014. Vol. 72, No. 12. P. 763–773. DOI: 10.1111/nure.12155

[57] Iijima H, Tomizawa Y, Iwasaki Y, et al. Genetic and epigenetic inactivation of LTF gene at 3p21.3 in lung cancers. Int J Cancer. 2006;118(4):797–801. DOI: 10.1002/ijc.21462

[58] Iijima H., Tomizawa Y., Iwasaki Y. et al. Genetic and epigenetic inactivation of LTF gene at 3p21.3 in lung cancers // Int. J. Cancer. 2006. Vol. 118, No. 4. P. 797–801. DOI: 10.1002/ijc.21462

[59] Mariller C, Hardivillé S, Hoedt E, et al. Delta-lactoferrin, an intracellular lactoferrin isoform that acts as a transcription factor. Biochem Cell Biol. 2012;90(3):307–319. DOI: 10.1139/o11-070

[60] Mariller C., Hardivillé S., Hoedt E. et al. Delta-lactoferrin, an intracellular lactoferrin isoform that acts as a transcription factor // Biochem. Cell Biol. 2012. Vol. 90, No. 3. P. 307–319. DOI: 10.1139/o11-070

[61] Porter CM, Haffner MC, Kulac I, et al. Lactoferrin CpG island hypermethylation and decoupling of mRNA and protein expression in the early stages of prostate carcinogenesis. Am J Pathol. 2019;189(11):2311–2322. DOI: 10.1016/j.ajpath.2019.07.016

[62] Porter C.M., Haffner M.C., Kulac I. et al. Lactoferrin CpG island hypermethylation and decoupling of mRNA and protein expression in the early stages of prostate carcinogenesis // Am. J. Pathol. 2019. Vol. 189, No. 11. P. 2311–2322. DOI: 10.1016/j.ajpath.2019.07.016

[63] Zhou Y, Zeng Z, Zhang W, et al. Lactotransferrin: a candidate tumor suppressor-Deficient expression in human nasopharyngeal carcinoma and inhibition of NPC cell proliferation by modulating the mitogen-activated protein kinase pathway. Int J Cancer. 2008;123(9):2065–2072. DOI: 10.1002/ijc.23727

[64] Zhou Y., Zeng Z., Zhang W. et al. Lactotransferrin: a candidate tumor suppressor-deficient expression in human nasopharyngeal carcinoma and inhibition of NPC cell proliferation by modulating the mitogen-activated protein kinase pathway // Int. J. Cancer. 2008. Vol. 123, No. 9. P. 2065–2072. DOI: 10.1002/ijc.23727

[65] Zalutskii IV, Lukianova NY, Storchai DM, et al. Influence of exogenous lactoferrin on the oxidant/antioxidant balance and molecular profile of hormone receptor-positive and -negative human breast cancer cells in vitro. Exp Oncol. 2017;39(2):106–111.

[66] Zalutskii I.V., Lukianova N.Y., Storchai D.M. et al. Influence of exogenous lactoferrin on the oxidant/antioxidant balance and molecular profile of hormone receptor-positive and -negative human breast cancer cells in vitro // Exp. Oncol. 2017. Vol. 39, No. 2. P. 106–111.

[67] Li HY, Li P, Yang HG, et al. Investigation and comparison of the anti-tumor activities of lactoferrin, α-lactalbumin, and β-lactoglobulin in A549, HT29, HepG2, and MDA231-LM2 tumor models. J Dairy Sci. 2019;102(11):9586–9597. DOI: 10.3168/jds.2019-16429

[68] Li H.Y., Li P., Yang H.G. et al. Investigation and comparison of the anti-tumor activities of lactoferrin, α-lactalbumin, and β-lactoglobulin in A549, HT29, HepG2, and MDA231-LM2 tumor models // J. Dairy Sci. 2019. Vol. 102, No. 11. P. 9586–9597. DOI: 10.3168/jds.2019-16429

[69] Li H, Yao Q, Min L, et al. The Combination of two bioactive constituents, lactoferrin and linolenic acid, inhibits mouse xenograft esophageal tumor growth by downregulating lithocholyltaurine and inhibiting the JAK2/STAT3-related pathway. ACS Omega. 2020;5(33):20755–20764. DOI: 10.1021/acsomega.0c01132

[70] Li H., Yao Q., Min L. et al. The combination of two bioactive constituents, lactoferrin and linolenic acid, inhibits mouse xenograft esophageal tumor growth by downregulating lithocholyltaurine and inhibiting the JAK2/STAT3-related pathway // ACS Omega. 2020. Vol. 5, No. 33. P. 20755–20764. DOI: 10.1021/acsomega.0c01132

[71] Elizarova A, Sokolov A, Kostevich V, et al. Interaction of lactoferrin with unsaturated fatty acids: In vitro and in vivo study of human lactoferrin/oleic acid complex cytotoxicity. Materials (Basel). 2021;14(7):1602. DOI: 10.3390/ma14071602

[72] Elizarova A., Sokolov A., Kostevich V. et al. Interaction of lactoferrin with unsaturated fatty acids: in vitro and in vivo study of human lactoferrin/oleic acid complex cytotoxicity // Materials (Basel). 2021. Vol. 14, No. 7. P. 1602. DOI: 10.3390/ma14071602

[73] Cutone A, Rosa L, Ianiro G, et al. Lactoferrin’s anti-cancer properties: safety, selectivity, and wide range of action. Biomolecules. 2020;10(3):456. DOI: 10.3390/biom10030456

[74] Cutone A., Rosa L., Ianiro G. et al. Lactoferrin’s anti-cancer properties: safety, selectivity, and wide range of action // Biomolecules. 2020. Vol. 10, No. 3. P. 456. DOI: 10.3390/biom10030456

[75] Eliassen LT, Berge G, Leknessund A, et al. The antimicrobial peptide, lactoferricin B, is cytotoxic to neuroblastoma cells in vitro and inhibits xenograft growth in vivo. Int J Cancer. 2006;119(3):493–500. DOI: 10.1002/ijc.21886

[76] Eliassen L.T., Berge G., Leknessund A. et al. The antimicrobial peptide, lactoferricin B, is cytotoxic to neuroblastoma cells in vitro and inhibits xenograft growth in vivo // Int. J. Cancer. 2006. Vol. 119, No. 3. P. 493–500. DOI: 10.1002/ijc.21886

[77] Arcella A, Oliva MA, Staffieri S, et al. In vitro and in vivo effect of human lactoferrin on glioblastoma growth. J Neurosurg. 2015;123(4):1026–1035. DOI: 10.3171/2014.12.JNS14512

[78] Arcella A., Oliva M.A., Staffieri S. et al. In vitro and in vivo effect of human lactoferrin on glioblastoma growth // J. Neurosurg. 2015. Vol. 123, No. 4. P. 1026–1035. DOI: 10.3171/2014.12.JNS14512

[79] Verduci E, Banderali G, Barberi S, et al. Epigenetic effects of human breast milk. Nutrients. 2014;6(4):1711–1724. DOI: 10.3390/nu6041711

[80] Verduci E., Banderali G., Barberi S. et al. Epigenetic effects of human breast milk // Nutrients. 2014. Vol. 6, No. 4. P. 1711–1724. DOI: 10.3390/nu6041711

[81] Zhang TN, Liu N. Effect of bovine lactoferricin on DNA methyltransferase 1 levels in Jurkat T-leukemia cells. J Dairy Sci. 2010;93(9):3925–3930. DOI: 10.3168/jds.2009-3024

[82] Zhang T.N., Liu N. Effect of bovine lactoferricin on DNA methyltransferase 1 levels in Jurkat T-leukemia cells // J. Dairy Sci. 2010. Vol. 93, No. 9. P. 3925–3930. DOI: 10.3168/jds.2009-3024

[83] Lebedev DV, Zabrodskaya YA, Pipich V, et al. Effect of alpha-lactalbumin and lactoferrin oleic acid complexes on chromatin structural organization. Biochem Biophys Res Commun. 2019;520(1):136–139. DOI: 10.1016/j.bbrc.2019.09.116

[84] Lebedev D.V., Zabrodskaya Y.A., Pipich V. et al. Effect of alpha-lactalbumin and lactoferrin oleic acid complexes on chromatin structural organization // Biochem. Biophys. Res. Commun. 2019. Vol. 520, No. 1. P. 136–139. DOI: 10.1016/j.bbrc.2019.09.116

[85] Jögi A, Øra I, Nilsson H, et al. Hypoxia alters gene expression in human neuroblastoma cells toward an immature and neural crest-like phenotype. Proc Natl Acad Sci USA. 2002;99(10):7021–7026. DOI: 10.1073/pnas.102660199

[86] Jögi A., Øra I., Nilsson H. et al. Hypoxia alters gene expression in human neuroblastoma cells toward an immature and neural crest-like phenotype // Proc. Natl. Acad. Sci. USA. 2002. Vol. 99, No. 10. P. 7021–7026. DOI: 10.1073/pnas.102660199

[87] Westerlund I, Shi Y, Toskasa K, et al. Combined epigenetic and differentiation-based treatment inhibits neuroblastoma tumor growth and links HIF2α to tumor suppression. Proc Natl Acad Sci USA. 2017;114(30):E6137–E6146. DOI: 10.1073/pnas.1700655114

[88] Westerlund I., Shi Y., Toskasa K. et al. Combined epigenetic and differentiation-based treatment inhibits neuroblastoma tumor growth and links HIF2α to tumor suppression // Proc. Natl. Acad. Sci. USA. 2017. Vol. 114, No. 30. P. e6137–e6146. DOI: 10.1073/pnas.1700655114

[89] Camuzi D, de Amorim Í, Ribeiro Pinto LF, et al. Regulationi in the air: the relationship between hypoxia and epigenetics in cancer. Cells. 2019;8(4):300. DOI: 10.3390/cells8040300

[90] Camuzi D., de Amorim Í., Ribeiro Pinto L.F. et al. Regulation is in the air: the relationship between hypoxia and epigenetics in cancer // Cells. 2019. Vol. 8, No. 4. P. 300. DOI: 10.3390/cells8040300

[91] D’Anna F, Van Dyck L, Xiong J, et al. DNA methylation repels binding of hypoxia-inducible transcription factors to maintain tumor immunotolerance. Genome Biol. 2020;21(1):182. DOI: 10.1186/s13059-020-02087-z

[92] D’Anna F., Van Dyck L., Xiong J. et al. DNA methylation repels binding of hypoxia-inducible transcription factors to maintain tumor immunotolerance // Genome Biol. 2020. Vol. 21, No. 1. P. 182. DOI: 10.1186/s13059-020-02087-z

[93] Sharrouf KA, Suchkova IO. The influence of lactoferrin on the epigenetic characteristics of mammalian cells of different types. Medical Academic Journal. 2021;21(1):85–95. DOI: 10.17816/MAJ64106

[94] Шаруфф К.А., Сучкова И.О. Влияние лактоферрина на эпигенетические характеристики клеток млекопитающих разного типа // Медицинский академический журнал. 2021. Т. 21. № 1. С. 85–95. DOI: 10.17816/MAJ6410

[95] Lebedev TD, Spirin PV, Orlova NN, et al. Comparative analysis of gene expression: Targeted antitumor therapy in neuroblastoma cell lines. Mol Biol (Mosk). 2015;49(6):1048–1051. (In Russ.) DOI: 10.1134/S0026893315050225

[96] Лебедев Т.Д., Спирин П.В., Орлова Н.Н. и др. Сравнительный анализ экспрессии генов-мишеней противоопухолевой терапии, в клеточных линиях нейробастомы // Молекулярная биология. 2015. Т. 49, № 6. С. 1048–1051. DOI: 10.7868/S0026898415050225

[97] Harenza JL, Diamond MA, Adams RN, et al. Transcriptomic profiling of 39 commonly-used neuroblastoma cell lines. Sci Data. 2017;4:170033. DOI: 10.1038/sdata.2017.33

[98] Harenza J.L., Diamond M.A., Adams R.N. et al. Transcriptomic profiling of 39 commonly-used neuroblastoma cell lines // Sci. Data. 2017. Vol. 4. P. 170033. DOI: 10.1038/sdata.2017.33

[99] Ram Kumar RM, Schor NF. Methylation of DNA and chromatin as a mechanism of oncogenesis and therapeutic target in neuroblastoma. Oncotarget. 2018;9(31):22184–22193. DOI: 10.18632/oncotarget.25084

[100] Ram Kumar R.M., Schor N.F. Methylation of DNA and chromatin as a mechanism of oncogenesis and therapeutic target in neuroblastoma // Oncotarget. 2018. Vol. 9, No. 31. P. 22184–22193. DOI: 10.18632/oncotarget.25084

[101] Polyanskaya GG, Sakuta GA, Yeropkin MY, et al. Katalog rossiyskoy kollektsii kletochnykh kul’tur pozvonochnykh (RKKK P). Saint Petersburg; 2018. [Internet]. Available from: https://incras.ru/wp-content/uploads/2022/05/katalog_rccc_v_2018_rus.pdf. Accessed: Feb 10, 2022. (In Russ.)

[102] Полянская Г.Г., Сакута Г.А., Еропкин М.Ю. и др. Каталог российской коллекции клеточных культур позвоночных (РККК П) [Электронный ресурс]. Санкт-Петербург, 2018. Режим доступа: https://incras.ru/wp-content/uploads/2022/05/katalog_rccc_v_2018_rus.pdf. Дата обращения 10.02.2022.

[103] Lee J-M, Anderson PC, Padgitt JK, et al. Nrf2, not the estrogen receptor, mediates catechol estrogen-induced activation of the antioxidant responsive element. Biochim Biophys Acta. 2003;1629(1–3):92–101. DOI: 10.1016/j.bbaexp.2003.08.006

[104] Lee J-M., Anderson P.C., Padgitt J.K. et al. Nrf2, not the estrogen receptor, mediates catechol estrogen-induced activation of the antioxidant responsive element // Biochim. Biophys. Acta. 2003. Vol. 1629, No. 1–3. P. 92–101. DOI: 10.1016/j.bbaexp.2003.08.006

[105] Su C, Rybalchenko N, Schreihofer DA, et al. Cell models for the study of sex steroid hormone Neurobiology. J Steroids Horm Sci. 2012;S2:003. DOI: 10.4172/2157-7536.s2-003

[106] Su C., Rybalchenko N., Schreihofer D.A. et al. Cell models for the study of sex steroid hormone neurobiology // J. Steroids Horm. Sci. 2012. Vol. S2. P. 003. DOI: 10.4172/2157-7536.s2-003

[107] El-Maarri O, Walier M, Behne F, et al. Methylation at global LINE-1 repeats in human blood are affected by gender but not by age or natural hormone cycles. PLoS One. 2011;6(1):e16252. DOI: 10.1371/journal.pone.0016252

[108] El-Maarri O., Walier M., Behne F. et al. Methylation at global LINE-1 repeats in human blood are affected by gender but not by age or natural hormone cycles // PLoS One. 2011. Vol. 6, No. 1. P. e16252. DOI: 10.1371/journal.pone.0016252

[109] Hsu CC, Leu YW, Tseng MJ, et al. Functional characterization of Trip10 in cancer cell growth and survival. J Biomed Sci. 2011;18:12. DOI: 10.1186/1423-0127-18-12

[110] Hsu C.C., Leu Y.W., Tseng M.J. et al. Functional characterization of Trip10 in cancer cell growth and survival // J. Biomed. Sci. 2011. Vol. 18. P. 12. DOI: 10.1186/1423-0127-18-12

[111] Semak I, Budzevich A, Maliushkova E, et al. Development of dairy herd of transgenic goats as biofactory for large-scale production of biologically active recombinant human lactoferrin. Transgenic Res. 2019;28(5–6):465–478. DOI: 10.1007/s11248-019-00165-y

[112] Semak I., Budzevich A., Maliushkova E. et al. Development of dairy herd of transgenic goats as biofactory for large-scale production of biologically active recombinant human lactoferrin // Transgenic Res. 2019. Vol. 28, No. 5–6. P. 465–478. DOI: 10.1007/s11248-019-00165-y

[113] Mitroshina EV, Mishchenko TA, Vedunova MV. Opredeleniye zhiznesposobnosti kletochnykh kul’tur: uchebno-metodicheskoye posobiye. Nizhniy Novgorod: Nizhegorodskiy gosuniversitet im. N.I. Lobachevskogo; 2015. (In Russ.)

[114] Митрошина Е.В., Мищенко Т.А., Ведунова М.В. Определение жизнеспособности клеточных культур: учебно-методическое пособие. Нижний Новгород: Нижегородский госуниверситет им. Н.И. Лобачевского, 2015.

[115] Suguna S, Nandal DH, Kamble S, et al. Genomic DNA isolation from human whole blood samples by non-enzymatic salting out method. Int J Pharm Pharmac Sci. 2014;6(6):198–199.

[116] Suguna S., Nandal D.H., Kamble S. et al. Genomic DNA isolation from human whole blood samples by non-enzymatic salting out method // Int. J. Pharm. Pharmac. Sci. 2014. Vol. 6, No. 6. P. 198–199.

[117] zymoresearch.com [Internet]. 5-mC DNA ELISA Kit. Available from: https://www.zymoresearch.com/products/5-mc-dna-elisa-kit. Accssed: Apr 05, 2022.

[118] zymoresearch.com [Электронный ресурс] 5-mC DNA ELISA Kit. Режим доступа: https://www.zymoresearch.com/products/ 5-mc-dna-elisa-kit. Дата обращения: 04.05.2022.

[119] Suchkova IO, Sasina LK, Dergacheva NI, et al. The influence of low dose bisphenol A on whole genome DNA methylation and chromatin compaction in different human cell lines. Toxicol In Vitro. 2019;58:26–34. DOI: 10.1016/j.tiv.2019.03.010

[120] Suchkova I.O., Sasina L.K., Dergacheva N.I. et al. The influence of low dose bisphenol A on whole genome DNA methylation and chromatin compaction in different human cell lines // Toxicol in Vitro. 2019. Vol. 58. P. 26–34. DOI: 10.1016/j.tiv.2019.03.010

[121] Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods. 2012;9(7):671–675. DOI: 10.1038/nmeth.2089

[122] Schneider C.A., Rasband W.S., Eliceiri K.W. NIH Image to ImageJ: 25 years of image analysis // Nat. Methods. 2012. Vol. 9, No. 7. P. 671–675. DOI: 10.1038/nmeth.2089

[123] Ling G, Waxman DJ. DNase I digestion of isolated nulcei for genome-wide mapping of DNase hypersensitivity sites in chromatin. Methods Mol Biol. 2013;977:21–33. DOI: 10.1007/978-1-62703-284-1_3

[124] Ling G., Waxman D.J. DNase I digestion of isolated nulcei for genome-wide mapping of DNase hypersensitivity sites in chromatin // Methods Mol. Biol. 2013. Vol. 977. P. 21–33. DOI: 10.1007/978-1-62703-284-1_3

[125] Lu Q, Richardson B. DNaseI hypersensitivity analysis of chromatin structure. Methods Mol Biol. 2004;287:77–86. DOI: 10.1385/1-59259-828-5:077

[126] Lu Q., Richardson B. DNase I hypersensitivity analysis of chromatin structure // Methods Mol. Biol. 2004. Vol. 287. P. 77–86. DOI: 10.1385/1-59259-828-5:077

[127] Keuser B, Khobta A, Galle K, et al. Influences of histone deacetylase inhibitors and resveratrol on DNA repair and chromatin compaction. Mutagenesis. 2013;28(5):569–576. DOI: 10.1093/mutage/get034

[128] Keuser B., Khobta A., Galle K. et al. Influences of histone deacetylase inhibitors and resveratrol on DNA repair and chromatin compaction // Mutagenesis. 2013. Vol. 28, No. 5. P. 569–576. DOI: 10.1093/mutage/get034

[129] VassarStats: Website for statistical computation [Internet]. Available from: http://vassarstats.net. Accessed: March 8, 2022.

[130] VassarStats. Website for statistical computation [Электронный ресурс]. Режим доступа: http://vassarstats.net. Дата обращения: 08.03.2022.

[131] Statistics Kingdom [Internet]. Available from: http://www.statskingdom.com. Accessed: March 8, 2022.

[132] Statistics Kingdom [Электронный ресурс]. Режим доступа: http://www.statskingdom.com. Дата обращения: 08.03.2022.

[133] BoxPlot online [Internet]. Available from: http://www.physics.csbsju.edu/stats/bulk.stats.n.plot_NGROUP_form.html. Accessed: Dec 15, 2020.

[134] BoxPlot online [Электронный ресурс]. Режим доступа: http://www.physics.csbsju.edu/stats/bulk.stats.n.plot_NGROUP_form.html. Дата обращения: 15.12.2020.

[135] Navendu Vasavada. Online web statistical calculators [Internet]. Available from: http://astatsa.com. Accessed: Apr 05, 2022.

[136] Navendu Vasavada. Online web statistical calculators. [Электронный ресурс]. Режим доступа: http://astatsa.com. Дата обращения: 05.04.2022.

[137] MNK i regressionnyi analiz Onlain [Internet]. Matematicheskii forum Math Help Planet. Available from: http://mathhelpplanet.com/static.php?p=onlayn-mnk-i-regressionniy-analiz. Accessed: Apr 05, 2022. (In Russ.)

[138] МНК и регрессионный анализ Онлайн [Электронный ресурс] // Математический форум Math Help Planet. Режим доступа: http://mathhelpplanet.com/static.php?p=onlayn-mnk-i-regressionniy-analiz. Дата обращения: 05.04.2022.

[139] Uravnenie nelineinoi regressii onlain [Internet]. OOO Novyi semestr. Available from: https://math.semestr.ru/corel/noncorel.php. Accessed: Apr 05, 2022. (In Russ.)

[140] Уравнение нелинейной регрессии онлайн [Электронный ресурс] // ООО Новый семестр. Режим доступа: https://math.semestr.ru/corel/noncorel.php. Дата обращения: 05.04.2022.

[141] Wessa P. Free Statistics Software. Office for Research Development and Education. version 1.2.1 [Internet]. Available from: https://www.wessa.net. Accessed: Apr 05, 2022.

[142] Wessa P. Free Statistics Software. Office for Research Development and Education. version 1.2.1 [Электронный ресурс]. Режим доступа: https://www.wessa.net. Дата обращения: 05.04.2022.

[143] Wessa P. Multivariate Correlation Matrix (v1.0.11) in Free Statistics Software (v1.2.1), Office for Research Development and Education. 2016 [Internet]. Available from: https://www.wessa.net/rwasp_pairs.wasp. Accessed: Apr 05, 2022.

[144] Wessa P. Multivariate Correlation Matrix (v1.0.11) in Free Statistics Software (v1.2.1), Office for Research Development and Education. 2016. [Электронный ресурс]. Режим доступа: https://www.wessa.net/rwasp_pairs.wasp. Дата обращения: 05.04.2022.

[145] Polynomial Regression Calculator [Internet]. Stats Blue. Available from: https://stats.blue/Stats_Suite/polynomial_regression_calculator.html. Accessed: Oct 13, 2022.

[146] Polynomial Regression Calculator [Электронный ресурс] // Stats Blue. Режим доступа: https://stats.blue/Stats_Suite/polynomial_regression_calculator.html. Дата обращения: 13.10.2022.

[147] Yanaihara A, Toma Y, Saito H, et al. Cell proliferation effect of lactoferrin in human endometrial stroma cells. Mol Hum Reprod. 2000;6(5):469–473. DOI: 10.1093/molehr/6.5.469

[148] Yanaihara A., Toma Y., Saito H., Yanaihara T. Cell proliferation effect of lactoferrin in human endometrial stroma cells // Mol. Hum. Reprod. 2000. Vol. 6, No. 5. P. 469–473. DOI: 10.1093/molehr/6.5.469

[149] Lorget F, Clough J, Oliveira M, et al. Lactoferrin reduces in vitro osteoclast differentiation and resorbing activity. Biochem Biophys Res Commun. 2002;296(2):261–266. DOI: 10.1016/s0006-291x(02)00849-5

[150] Lorget F., Clough J., Oliveira M. et al. Lactoferrin reduces in vitro osteoclast differentiation and resorbing activity // Biochem. Biophys. Res. Commun. 2002. Vol. 296, No. 2. P. 261–266. DOI: 10.1016/s0006-291x(02)00849-5

[151] Buccigrossi V, de Marco G, Bruzzese E, et al. Lactoferrin induces concentration-dependent functional modulation of intestinal proliferation and differentiation. Pediatr Res. 2007;61(4):410–414. DOI: 10.1203/pdr.0b013e3180332c8d

[152] Buccigrossi V., de Marco G., Bruzzese E. et al. Lactoferrin induces concentration-dependent functional modulation of intestinal proliferation and differentiation // Pediatr. Res. 2007. Vol. 61, No. 4. P. 410–414. DOI: 10.1203/pdr.0b013e3180332c8d

[153] Jiang R, Lopez V, Kelleher SL, et al. Apo- and holo-lactoferrin are both internalized by lactoferrin receptor via clathrin-mediated endocytosis but differentially affect ERK-signaling and cell proliferation in Caco-2 cells. J Cell Physiol. 2011;226(11):3022–3031. DOI: 10.1002/jcp.22650

[154] Jiang R., Lopez V., Kelleher S.L., Lönnerdal B. Apo- and holo-lactoferrin are both internalized by lactoferrin receptor via clathrin-mediated endocytosis but differentially affect ERK-signaling and cell proliferation in Caco-2 cells // J. Cell Physiol. 2011. Vol. 226, No. 11. P. 3022–3031. DOI: 10.1002/jcp.2265

[155] Babushkina NA, Ostrovskaya LA, Rykova VA, et al. Modelirovaniye effektivnosti deystviya protivoopukholevykh preparatov v sverkhmalykh dozakh dlya optimizatsii rezhimov vvedeniya. Control Sciences. 2005;4:47–54. (In Russ.)

[156] Бабушкина Н.А., Островская Л.А., Рыкова В.А. и др. Моделирование эффективности действия противоопухолевых препаратов в сверхмалых дозах для оптимизации режимов введения // Проблемы управления. 2005. Т. 4. С. 47–54.

[157] Generalenko NYu, Kryukova LYu, Pushkin IA. Effects of small and micro doses biologically active substances. Nauchnyye i obrazovatel’nyye problemy grazhdanskoy zashchity. 2010;3:6–7. (In Russ.)

[158] Генераленко Н.Ю., Крюкова Л.Ю., Пушкин И.А. Эффекты малых и сверхмалых доз биологически активных веществ // Научные и образовательные проблемы гражданской защиты. 2010. № 3. С. 6–7.

[159] Bellavite P, Ortolani R, Pontarollo F, et al. Immunology and homeopathy. 5. The rationale of the ‘Simile’. Evid Based Complement Alternat Med. 2007;4(2):149–163. DOI: 10.1093/ecam/nel117

[160] Bellavite P., Ortolani R., Pontarollo F. et al. Immunology and homeopathy. 5. The rationale of the ‘Simile’ // Evid. Based Complement. Alternat. Med. 2007. Vol. 4, No. 2. P. 149–163. DOI: 10.1093/ecam/nel117

[161] Utsugi T, Schroit AJ, Connor J, et al. Elevated expression of phosphatidylserine in the outer membrane leaflet of human tumor cells and recognition by activated human blood monocytes. Cancer Res. 1991;51(11):3062–3066.

[162] Utsugi T., Schroit A.J., Connor J. et al. Elevated expression of phosphatidylserine in the outer membrane leaflet of human tumor cells and recognition by activated human blood monocytes // Cancer Res. 1991. Vol. 51, No. 11. P. 3062–3066.

[163] Damiens E, El Yazidi I, Mazurier J, et al. Role of heparan sulphate proteoglycans in the regulation of human lactoferrin binding and activity in the MDA-MB-231 breast cancer cell line. Eur J Cell Biol. 1998;77(4):344–351. DOI: 10.1016/S0171-9335(98)80093-9

[164] Damiens E., El Yazidi I., Mazurier J. et al. Role of heparan sulphate proteoglycans in the regulation of human lactoferrin binding and activity in the MDA-MB-231 breast cancer cell line // Eur. J. Cell Biol. 1998. Vol. 77, No. 4. P. 344–351. DOI: 10.1016/S0171-9335(98)80093-9

[165] Antequera F. Structure, function and evolution of CpG island promoters. Cell Mol Life Sci. 2003;60(8):1647–1658. DOI: 10.1007/s00018-003-3088-6

[166] Antequera F. Structure, function and evolution of CpG island promoters // Cell Mol. Life Sci. 2003. Vol. 60, No. 8. P. 1647–1658. DOI: 10.1007/s00018-003-3088-6

[167] Lakshminarasimhan R, Liang G. The role of DNA methylation in cancer. Adv Exp Med Biol. 2016;945:151–172. DOI: 10.1007/978-3-319-43624-1_7

[168] Lakshminarasimhan R., Liang G. The role of DNA methylation in cancer // Adv. Exp. Med. Biol. 2016. Vol. 945. P. 151–172. DOI: 10.1007/978-3-319-43624-1_7

[169] Ball MP, Li JB, Gao Y, et al. Targeted and genome-scale strategies reveal gene-body methylation signatures in human cells. Nat Biotechnol. 2009;27(4):361–368. DOI: 10.1038/nbt.1533

[170] Ball M.P., Li J.B., Gao Y. et al. Targeted and genome-scale strategies reveal gene-body methylation signatures in human cells // Nat. Biotechnol. 2009. Vol. 27, No. 4. P. 361–368. DOI: 10.1038/nbt.1533

[171] Fazzari MJ, Greally JM. Epigenomics: beyond CpG islands. Nat Rev Genet. 2004;5(6):446–455. DOI: 10.1038/nrg1349

[172] Fazzari M.J., Greally J.M. Epigenomics: beyond CpG islands // Nat. Rev. Genet. 2004. Vol. 5, No. 6. P. 446–455. DOI: 10.1038/nrg1349

[173] Kulis M, Queirós AC, Beekman R, et al. Intragenic DNA methylation in transcriptional regulation, normal differentiation and cancer. Biochim Biophys Acta. 2013;1829(11):1161–1174. DOI: 10.1016/j.bbagrm.2013.08.001

[174] Kulis M., Queirós A.C., Beekman R., Martín-Subero J.I. Intragenic DNA methylation in transcriptional regulation, normal differentiation and cancer // Biochim. Biophys. Acta. 2013. Vol. 1829, No. 11. P. 1161–1174. DOI: 10.1016/j.bbagrm.2013.08.001

[175] Lou S, Lee HM, Qin H, et al. Whole-genome bisulfite sequencing of multiple individuals reveals complementary roles of promoter and gene body methylation in transcriptional regulation. Genome Biol. 2014;15(7):408. DOI: 10.1186/s13059-014-0408-0

[176] Lou S., Lee H.M., Qin H. et al. Whole-genome bisulfite sequencing of multiple individuals reveals complementary roles of promoter and gene body methylation in transcriptional regulation // Genome Biol. 2014. Vol. 15, No. 7. P. 408. DOI: 10.1186/s13059-014-0408-0

[177] Nagarajan RP, Zhang B, Bell RJ, et al. Recurrent epimutations activate gene body promoters in primary glioblastoma. Genome Res. 2014;24(5):761–774. DOI: 10.1101/gr.164707.113

[178] Nagarajan R.P., Zhang B., Bell R.J. et al. Recurrent epimutations activate gene body promoters in primary glioblastoma // Genome Res. 2014. Vol. 24, No. 5. P. 761–774. DOI: 10.1101/gr.164707.113

[179] Gurova KV. Chromatin stability as a target for cancer treatment. Bioessays. 2019;41(1):e1800141. DOI: 10.1002/bies.201800141

[180] Gurova K.V. Chromatin stability as a target for cancer treatment // Bioessays. 2019. Vol. 41, No. 1. P. e1800141. DOI: 10.1002/bies.201800141

[181] Furmanski P, Li ZP, Fortuna MB, et al. Multiple molecular forms of human lactoferrin. Identification of a class of lactoferrins that possess ribonuclease activity and lack iron-binding capacity. J Exp Med. 1989;170(2):415–429. DOI: 10.1084/jem.170.2.415

[182] Furmanski P., Li Z.P., Fortuna M.B. et al. Multiple molecular forms of human lactoferrin. Identification of a class of lactoferrins that possess ribonuclease activity and lack iron-binding capacity // J. Exp. Med. 1989. Vol. 170, No. 2. P. 415–429. DOI: 10.1084/jem.170.2.415

[183] Talks KL, Turley H, Gatter KC, et al. The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages. Am J Pathol. 2000;157(2):411–421. DOI: 10.1016/s0002-9440(10)64554-3

[184] Talks K.L., Turley H., Gatter K.C. et al. The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages // Am. J. Pathol. 2000. Vol. 157, No. 2. P. 411–421. DOI: 10.1016/s0002-9440(10)64554-3

[185] Zhong H, De Marzo AM, Laughner E, et al. Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res. 1999;59(22):5830–5835.

[186] Zhong H., De Marzo A.M., Laughner E. et al. Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases // Cancer Res. 1999. Vol. 59, No. 22. P. 5830–5835.

[187] Kostevich VA, Sokolov AV, Kozlov SO, et al. Functional link between ferroxidase activity of ceruloplasmin and protective effect of apo-lactoferrin: studying rats kept on a silver chloride diet. Biometals. 2016;29(4):691–704. DOI: 10.1007/s10534-016-9944-2

[188] Kostevich V.A., Sokolov A.V., Kozlov S.O. et al. Functional link between ferroxidase activity of ceruloplasmin and protective effect of apo-lactoferrin: studying rats kept on a silver chloride diet // Biometals. 2016. Vol. 29, No. 4. P. 691–704. DOI: 10.1007/s10534-016-9944-2

[189] Ibuki M, Shoda C, Miwa Y, et al. Lactoferrin has a therapeutic effect. Front Pharmacol. 2020;11:174. DOI: 10.3389/fphar.2020.00174

[190] Ibuki M., Shoda C., Miwa Y. et al. Lactoferrin has a therapeutic effect // Front. Pharmacol. 2020. Vol. 11. P. 174. DOI: 10.3389/fphar.2020.00174

RIGHTS & PERMISSIONS

Eco-Vector