Manifestation of Key Molecular Genetic Markers in Pharmacocorrection of Endogenous Iron Metabolism in MCF-7 and MCF-7/DDP Human Breast Cancer Cells


Effects of the nanocomposite and its components (magnetic fluid, cisplatin) on the level of endogenous iron exchange and the key links of genetic and epigenetic regulation of apoptotic program of sensitive and resistant MCF-7 cells were examined. We showed genetic and epigenetic mechanisms of action of nanocomposite of magnetic fluid and cisplatin. Nanocomposite caused elevation of number of cells in apoptosis in sensitive and especially resistant MCF-7 cells compared to cisplatin alone. It was proved that impact of nanocomposite on MCF-7/S and MCF-7/DDP cells caused more significant changes in expression of apoptosis regulators p53, Bcl-2 and Bax. We also suggested that changes in endogenous iron homeostasis and activation of free radical processes caused significant impact on apoptosis. Those changes included changes in methylation and expression of transferrin, its receptors, ferritin heavy and light chains (predominantly in resistant cell line), which caused activation of free radical synthesis and development of oxidative stress. We also showed that nanocomposite impact resulted into significant changes in expression of miRNA-34a and miRNA-200b, which regulated apoptosis, cell adhesion, invasion and activity of ferritin heavy chains gene. Thus, use of nanocomposite containing cisplatin and ferromagnetic as exogenous source of Fe ions caused changes of endogenous iron levels in sensitive and resistant cells allowing to increase specific activity of cytostatics and overcome factors, which promoted MDR development. Pharmacocorrection of endogenous iron metabolism allowed increasing antitumor activity of cisplatin and overcoming drug resistance.

Share and Cite:

Chekhun, V. , Lukianova, N. , Demash, D. , Borikun, T. , Chekhun, S. and Shvets, Y. (2013) Manifestation of Key Molecular Genetic Markers in Pharmacocorrection of Endogenous Iron Metabolism in MCF-7 and MCF-7/DDP Human Breast Cancer Cells. CellBio, 2, 217-227. doi: 10.4236/cellbio.2013.24025.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] V. Almendro, A. Marusyk and K. Polyak, “Cellular Heterogeneity and Molecular Evolution in Cancer,” Annual Review of Pathology—Mechanisms of Disease, Vol. 8, 2013, pp. 277-302.
[2] M. H. Barcellos-Hoff, “Does Microenvironment Contribute to the Etiology of Estrogen Receptor-Negative Breast Cancer?” Clinical Cancer Research, Vol. 19, No. 3, 2013, pp. 541-548.
[3] V. F. Chekhun, S. D. Sherban and Z. D. Savtsova, “Tumor Heterogeneity—Dynamical State,” Oncology, Vol. 14, No. 1, 2012, pp. 4-12.
[4] V. F. Chekhun, “From System Cancer Biology to Personalized Treatment,” Oncology, Vol. 14, No. 2, 2012, pp. 84-88.
[5] N. A. Saunders, F. Simpson, E. W. Thompson, M. M. Hill, L. Endo-Munoz, G. Leggatt, R. F. Minchin and A. Guminski, “Role of Intratumoural Heterogeneity in Cancer Drug Resistance: Molecular and Clinical Perspectives,” EMBO Molecular Medicine, Vol. 4, No. 8, 2012, pp. 675-684.
[6] T. V. Bagnyukova, I. P. Pogribny and V. F. Chekhun, “MicroRNAs in Normal and Cancer Cells: A New Class of Gene Expression Regulators,” Experimental Oncology, Vol. 28, No. 4, 2006, pp. 263-269.
[7] K. R. Kutanzi, O. V. Yurchenko, F. A. Beland, V. F. Checkhun and I. P. Pogribny, “MicroRNA-Mediated Drug Resistance in Breast Cancer,” Clinical Epigenetics, Vol. 2, No. 2, 2011, pp. 171-185.
[8] T. A. Farazi, J. I. Hoell, P. Morozov and T. Tusch, “MicroRNAs in Human Cancer,” Advances in Experimental Medicine and Biology, Vol. 774, 2013, pp. 1-20.
[9] S. Toyokuni, “Iron and Carcinogenesis: From Fenton Reaction to Target Genes,” Redox Report, Vol. 7, No. 4, 2002, pp. 189-197.
[10] P. Karihtala and Y. Soini, “Reactive Oxygen Species and Antioxidant Mechanisms in Human Tissues and Their Relation to Malignancies,” APMIS, Vol. 115, No. 2, 2007, pp. 81-103.
[11] H. Wiseman and B. Halliwell, “Damage to DNA by Reactive Oxygen and Nitrogen Species: Role in Inflammatory Disease and Progression to Cancer,” Biochemical Journal, Vol. 313, No. 1, 1996, pp. 17-29.
[12] S. I. Shpyleva, V. P. Tryndyak, O. Kovalchuk, A. Starlard-Davenport, V. F. Chekhun, F. A. Beland and I. P. Pogribny, “Role of Ferritin Alterations in Human Breast Cancer Cells,” Breast Cancer Research and Treatment, Vol. 126, No. 1, 2011, pp. 63-71.
[13] K. Fan, L. Gao and X. Yan, “Human Ferritin for Tumor Detection and Therapy,” Wiley Interdisciplinary Reviews Nanomedicine and Nanobiotechnology, Vol. 5, No. 4, 2013, pp. 287-298.
[14] C. Datz, T. K. Felder, D. Niederseer and E. Aigner, “Iron Homeostasis in the Metabolic Syndrome,” European Journal of Clinical Investigation, Vol. 43, No. 2, 2013, pp. 215-224.
[15] E. C. Theil, R. K. Behera and T. Tosha, “Ferritins for Chemistry and for Life,” Coordination Chemistry Reviews, Vol. 257, No. 2, 2013, pp. 579-586.
[16] M. Geppert, M. C. Hohnholt, S. Nürnberger and R. Dringen, “Ferritin Up-Regulation and Transient ROS Production in Cultured Brain Astrocytes after Loading with Iron Oxide Nanoparticles,” Acta Biomaterialia, Vol. 8, No. 10, 2012, pp. 3832-3839.
[17] V. F. Chekhun, N. Yu. Lukianova and N. O. Bezdene- zhnykh, “Features of Iron Metabolism Regulatingproteins Expression in Sensitive and Resistant to Antitumor Drugs Breast Cancer Cells in Vitro,” Clinical Oncology (SE), Proceedings of XII Ukrainian Oncologists Meeting, Sudak, 2011, p. 227.
[18] N. Kikyo, M. Suda, N. Kikyo, K. Hagiwara, K. Yasukawa, M. Fujisawa, Y. Yazaki and T. Okabe, “Purification and Characterization of a Cell Growth Factor from a Human Leukemia Cell Line: Immunological Identity with Ferritin,” Cancer Research, Vol. 54, No. 1, 1994, pp. 268-271.
[19] E. Laqué-Rupérez, M. J. Ruiz-Gómez, L. de la Pena, L. Gil and M. Martínez-Morillo, “Methotrexate Cytotoxicity on MCF-7 Breast Cancer Cells Is Not Altered by Exposure to 25 Hz, 1.5 mT Magnetic Field and Iron (III) Chloride Hexahydrate,” Bioelectrochemistry, Vol. 60, No. 1-2, 2003, pp. 81-86.
[20] J. F. Head, F. Wang and R. L. Elliott, “Antineoplastic Drugs That Interfere with Iron Metabolism in Cancer Cells,” Advances in Enzyme Regulation, Vol. 37, 1997, pp. 147-169.
[21] S. V. Torti and F. M. Torti, “Cellular Iron Metabolism in Prognosis and Therapy of Breast Cancer,” Critical Reviews in Oncogenesis, Vol. 18, No. 5, 2013, pp. 435-448.
[22] J. L. Heath, J. M. Weiss, C. P. Lavau and D. S. Wechsler, “Iron Deprivation in Cancer-Potential Therapeutic Implications,” Nutrients, Vol. 5, No. 8, 2013, pp. 2836-2859.
[23] M. Niks and M. Otto, “Towards an Optimized MTT Assay,” Journal of Immunological Methods, Vol. 130, No. 1, 1990, pp. 149-151.
[24] Y. L. Chao, C. R. Shepard and A. Wells, “Breast Carcinoma Cells Re-Express E-Cadherin during Mesenchymal to Epithelial Reverting Transition,” Molecular Cancer, Vol. 9, No. 1, 2010, pp. 179-197.
[25] R. A. McCelland, D. Wilson and R. Leake, “A Multicentre Study into the Reliability of Steroid Receptor Immunocyto-Chemical Assay Quantification,” European Journal of Cancer, Vol. 27, 1991, pp. 711-715.
[26] V. F. Chekhun, O. V. Yurchenko, L. A. Naleskina, D. V. Demash, N. Yu. Lukianova and Yu. V. Lozovska, “In Vitro Modification of Cisplatin Cytotoxicity with Magnetic Fluid,” Experimental Oncology, Vol. 35, No. 1, 2013, pp. 15-19.
[27] N. Yu. Lukyanova, N. V. Rusetskаya and N. A. Tregubova, “Moleсular Profile and Cell Cycle in MCF-7 Cells Resistant to Cisplatin and Doxorubicin,” Experimental Oncology, Vol. 31, No. 2, 2009, pp. 87-92.
[28] A. Jordan and P. Reichard, “Ribonucleotide Reductases,” Annual Review of Biochemistry, Vol. 67, 1998, pp. 71-98.
[29] H. Tanaka, H. Arakawa, T. Yamaguchi, K. Shiraishi, S. Fukuda, K. Matsui, Y. Takei and Y. Nakamura, “A Ribonucleotide Reductase Gene Involved in a p53-Dependent Cellcycle Checkpoint for DNA Damage,” Nature, Vol. 404, 2000, pp. 42-49.
[30] D. S. Byun, K. S. Chae, B. K. Ryu, M. G. Lee and S. G. Chi, “Expression and Mutation Analyses of P53R2, a Newly Identified p53 Target for DNA Repair in Human Gastric Carcinoma,” International Journal of Cancer, Vol. 98, No. 5, 2002, pp. 718-723.
[31] N. Yu. Lukianova, L. A. Naleskina, N. O. Bezdenezhnykh, L. M. Kunskaya, D. V. Demash, Yu. V. Yanish, I. M. Todor and V. F. Chekhun, “Reactive Changes of Cytophysiological Properties, Molecular-Biological Profile and Functional Metabolic Status of Cells in Vitro with Different Sensitivity to Cytostatic Agents under the Influence of Magnetic Fluid,” Journal of Cancer Research, Vol. 1, No. 1, 2013, pp. 7-14.
[32] H.-J. Kim, J.-H. Lee, S.-J. Kim, G. S. Oh, H.-D. Moon, K.-B. Kwon, C. Park, B. H. Park, H.-K. Lee, S.-Y. Chung, R. Park and H.-S. So, “Roles of NADPH Oxidases in Cisplatin-Induced Reactive Oxygen Species Generation and Ototoxicity,” The Journal of Neuroscience, Vol. 30, No. 11, 2010, pp. 3933-3946.
[33] A. Cozzi, B. Corsi, S. Levi, P. Santambrogio, G. Biasiotto and P. Arosi, “Analysis of the Biologic Functions of H- and L-Ferritins in HeLa Cells by Transfection with siRNAs and cDNAs: Evidence for a Proliferative Role of L-Ferritin,” Blood, Vol. 103, No. 6, 2004, pp. 2377-2383.
[34] X. Xu, H. L. Persson and D. R. Richardson, “Molecular Pharmacology of the Interaction of Anthracyclines with Iron,” Molecular Pharmacology, Vol. 68, No. 2, 2005, pp. 261-271.
[35] E. Pawelczyk, A. S. Arbab, S. Pandit, E. Hu and J. A. Frank, “Expression of Transferrin Receptor and Ferritin Following Ferumoxides-Protamine Sulfate Labeling of Cells: Implications for Cellular Magnetic Resonance Imaging,” NMR in Biomedicine, Vol. 19, 2006, pp. 581-592.
[36] H. M. O’Hagan, W. Wang, S. Sen, C. D. Shields, S. S. Lee, Y. W. Zhang, E. G. Clements, Y. Cai, L. Van Neste, H. Easwaran, R. A. Casero, C. L. Sears and S. B. Baylin, “Oxidative Damage Targets Complexes Containing DNA Methyltransferases, SIRT1, and Polycomb Members to Promoter CpG Islands,” Cancer Cell, Vol. 20, No. 5, 2011, pp. 606-619.

Copyright © 2024 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.