Abstract

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.

Highlights

  • After cultivation we studied expression of endogenous iron metabolism proteins, apoptosis regulators, CpG-sites methylation in promoters of ferritin heavy chains and transferrin receptor 1 genes, pool of reactive oxygen species (ROS), number of cells in apoptosis and necrosis, and expression of miRNA which regulate apoptosis, cell adhesion and activity of ferritin heavy chains

  • It has been clearly demonstrated that the effectiveness of most anti-tumor drugs (ATDR) depends on the depth of DNA violation or other cellular targets damages, but it is associated with the apoptotic program induction, cells’ oxidative stress, impaired structural and functional

  • It was shown that the formation of the phenotype of drug resistance to DDP is accompanied by impaired protein metabolism of endogenous iron: increased expression of regulatory-proteins of transmembrane transport (TFR1), cell influx of iron (Tf) and ferritin (FTL, ferritin heavy chains (FTH)) as a protein of intracellular iron storage and deposition (Figure 1, Table 5)

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Summary

Introduction

A new round of research in the field of tumor cells’ biology significantly changed the common view about the latent period of malignancy, its clinical and morphological classification, characteristics of the proliferative and metastatic potential, and the selection of treatment, the criteria for disease-free and overall patients’ survival.If, for example, we consider only the cellular heterogeneity and microenvironment in tumor tissue, modern immunohistochemical subtypes from basal and luminal A/B to “triple negative” breast cancer are just like surrogate analogues of real molecular genetic characteristics that can be significant for clinical oncology [1,2].One of the basic reasons for the heterogeneity of tumor tissue is the genetic and genomic instability caused by DNA sequence violations and rearrangement of chromosomes that determine the level of oncogenes and expression of tumor suppressors [3,4].Increased expression of certain genes and reduction of others constantly change their dynamic balance, which determines the degree of heterogeneity, and the level of sensitivity to therapy [5].The emergence of these changes is predominantly associated with violation of the program of epigenetic regulation of tumor cell, which is accompanied by general hypomethylation and hypermethylation of promoters of individual genes. One of the basic reasons for the heterogeneity of tumor tissue is the genetic and genomic instability caused by DNA sequence violations and rearrangement of chromosomes that determine the level of oncogenes and expression of tumor suppressors [3,4]. Increased expression of certain genes and reduction of others constantly change their dynamic balance, which determines the degree of heterogeneity, and the level of sensitivity to therapy [5]. The emergence of these changes is predominantly associated with violation of the program of epigenetic regulation of tumor cell, which is accompanied by general hypomethylation and hypermethylation of promoters of individual genes. The rapid progress in studying of epigenetic regulation mechanisms of gene expression revealed regulatory role of small miRNA molecules, Open Access

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