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One of the factors associated with increased morbidity of malignant neoplasms is environmental pollution with cancerogenic compounds including pesticides. Until recently, stable organic pollutant insecticide dichlorodiphenyltrichloroethane (DDT) was the single tool for fighting malaria carriers. Despite vast evidence of its negative effect on human health, DDT is still used in some countries.Aim. To perform a comprehensive analysis of the dynamics of DDT pesticide use and the consequences of its use on the global healthcare as well as to investigate the mechanism of its action on the human body including the endocrine system and cancerogenic effects.The review was composed using the PubMed (2853 publications), Elsevier (3139 publications), eLibrary (784 publications) biomedical literature databases. Full-text articles were retrieved through PubMed Central (PMC), Science Direct, Research Gate, CyberLeninka electronic resources.

Background. DNA methylation is a crucial mechanism of epigenetic regulation of transcription. Disturbances in DNA methylation mechanism are associated with various malignancies such as acute myeloid leukaemia, breast cancer, prostate cancer, etc. Influencing the functional status of DNA methyltransferases (DNMTs) enzymes and TET family proteins (TETs), which regulate DNA methylation and demethylation, is the basis of epigenetic anticancer therapy approach. In this review, we have considered the challenges and prospects of nucleoside and non-nucleoside inhibitors of DNMTs as well as TETs inhibitors. The results of clinical trials on the efficacy of DNMTs inhibitors used individually and as part of combination chemotherapy conducted over the last 15 years are also evaluated. Material and Methods. Sources were searched in PubMed, ScienceDirect, Web of Science, eLibrary, CyberLeninka. More than 700 publications were used in the analysis, but the review included mainly works of the last 10 years. A number of articles published earlier than 2015 were used for historical reference. Results. The review provides information on current advances in the development and study of epigenetically active compounds whose action is aimed at the regulation of DNA methylation. Data on the in vitro and in vivo effects of agents considered for use in the therapy of various malignancies are presented. In addition, the data of clinical trials of the most promising epigenetic modulators are presented.

The development of omics technologies and sequencing has significantly expanded the understanding of the role of microorganisms that inhabit various human organs and collectively make up its microbiota in the development of cancer. The extensive literature of recent years devoted to various aspects of the participation of the microbiota in carcinogenesis substantiates the relevance of analyzing the impact of its features on the processes of carcinogenesis in various human organs.Purpose of the study. Analysis of literature data on the key issues of the relationship between the human microbiome and the risk of cancer and explore possible prospects for its use in the diagnosis, therapy and prevention of cancer.Materials and methods. A literature search was carried out in the databases NCBI MedLine (PubMed), Scopus, Web of Science, based on an extended list of keywords that included all the localizations of malignant neoplasms (MNs) considered in the review. Original studies, meta-analyses, randomized controlled trials, and reviews published in recent years were used.Results. Recent studies using omics technologies have shown significant differences in the composition of microbial communities of healthy and tumor tissues and have made it possible to characterize the potential tumor microbiota in some types of cancer. The microbiota present in the various organs of the human body forms a network through which it interacts via migration or by forming metabolic axes between organs. Dysbiosis plays an important role in carcinogenesis, and its presence in one organ can negatively affect the condition of other distant organs and contribute to the development of pathological conditions in them.Conclusion. Numerous studies conducted over the past decade have revealed a complex relationship between microorganisms, tumors, and the host, reflecting the diverse effects of the microbiota on various organ- specific types of MNs. Gastrointestinal tract tumors, as well as sites outside it with significant bacterial associations, have been identified for a better understanding of the multifaceted mechanisms by which the microbiota influences cancer. The data obtained so far complement the emerging possibilities of using the microbiota in clinical practice, which represents a new approach to the prevention and treatment of malignant neoplasms.

In preparing the review, articles on the functioning of the reverse transcriptase enzyme of endogenous repeat sequences LINE1, the mechanisms of action and antitumor activity of viral reverse transcriptase inhibitors. Articles available in the biomedical literature information databases SciVerse Scopus, PubMed, Web of Science, Russian Science CitationIndex (RSCI) were analyzed. The review used information from 140 publications, of which 95 and 39 were published, respectively, over the last ten and three years, 2 articles present the results of clinical studies, and 45 articles refer to results demonstrating the anticancer properties of the studied compounds in various models in vitro and in vivo. Aim. Based on data on the functional properties of the reverse transcriptase enzyme of endogenous repeat sequences LINE1 (long interspersed nuclear elements 1), analyze the potential use of viral reverse transcriptase inhibitors in oncology, presenting their classification and main mechanisms of action. About 98 % of the human genome consists of repetitive sequences, most of which are represented by mobil genetic elements, the activation of which leads to increased genome instability. These include long (LINE) and short (SINE) interspersed nuclear element repeated DNA sequences interspersed nuclear elements, respectively, which occupy about 45 % of the human genome. Increased expression levels of these sequences in the genome have been identified in many forms of malignant neoplasms. Their transposition occurs due to the expression of LINE1-encoded reverse transcriptase, whichis homologous to viral reverse transcriptase. To date, reverse transcriptase inhibitors of viruses of nucleoside and non-nucleoside structure have been developed and are successfully used in the clinic. These drugs demonstrate an inhibitory effect on both LINE1 reverse transcriptase and telomerase, which provides the tumor cell with the ability to overcome replicative senescence. Due to these properties, these compounds are expected to exhibit both their own antitumor activity and increase the sensitivity of tumor cells to the therapy of malignant neoplasms, which is experimentally confirmed in models of malignant tumors in vitro and in vivo. Use of reverse transcriptase inhibitors in combination therapy seems advisable both to prevent further genome rearrangements caused by LINE1 and to suppress the survival of tumor cells by inhibiting telomerase activity.

The main aim of the study is to analyze modern knowledge on endocrine disruptors, non-genotoxic carcinogens, contributing significantly to the total level of contamination of the biosphere by anthropogenic blastomogens.Material and Methods. For the review preparation, we analyzed articles on molecular mechanisms of the effects of endocrine disruptors, available at biomedical literature databases sciVerse scopus, pubmed, Web of science, Rsci. The review cited 65 recent publications, 21 of them being published over the past three years, 3 papers being the official documents on hazards associated with the use of endocrine disruptors, and 10 papers presenting a background to separate endocrine disruptors into the group of compounds with specific functional activity.Results. The role of endocrine disruptors involves the development of the tumors of reproductive organs. They may reveal the properties of strong agonists or antagonists disrupting the hormonal balance by inhibition of the synthesis of natural hormones, their secretion, transport, metabolism, binding or degradation. In addition, they activate alternative proliferation signaling pathways by activating g-proteincoupled receptors, estrogen-bound eRRγ or/and β-adrenergic receptors. The main mechanism of action of endocrine disruptors is the induction of epigenetic modifications, in particular, methylation/demethylation of cpg dNa islands, histone modifications and changes in expression of non-coding RNa. since the effects of endocrine disruptors are nonlinear, they can be caused by concentrations corresponding to the real content in the biosphere and detected in the umbilical blood and breast milk. In addition, they contribute to the metabolic activation of the procarcinogens, the main component of air pollution, by activation of the cytochrome p450 isoforms.Conclusion. Endocrine disruptors can underlie the development of tumors of hormone-dependent organs both at direct and transplacental exposure.

The incidence and mortality of malignant neoplasms of non-reproductive organs both carcinomas and sarcomas in men is one and a half times higher than in women. This is based on genetic differences, which are superimposed by patterns of epigenetic regulation of the expression of sex chromosome genes that determine sex differences in the processes of tissue differentiation, which, in turn, mediates the formation of the hormonal status of the body. Compared to the Y chromosome, the mammalian X chromosome contains several dozen times more genes encoding major regulators of proliferation, metabolism, immunity, and tumor growth inhibitors, as well as X-linked microRNAs affecting transcription factors and cross-regulation by other non-coding RNAs. This results in a female or male gene expression profile that accounts for phenotypic differences. This peculiarity, along with the fact that in female cells on the second inactivatedX chromosome epigenetic repression of the most important genes is reversed and, accordingly, their expression level is doubled, may largely explain the sex disparity in carcinogenesis. The influence of sex hormones and disparity in the expression of antitumor immunity contribute significantly to this difference. A detailed study of the mechanisms underlying sex dimorphism in carcinogenesis will be an essential contribution to fundamental oncology and to the practice of diagnosis, prognosis and personalized treatment of malignances with regard to their gender-specific course. These studies are especially relevant in relation to insufficiently studied soft tissue sarcomas, the ratio of the frequencies of which in men and women varies greatly depending on the histological subtype of the tumor.

Genetic apparatus of human cells is constantly affected by a broad spectrum of mutagenic factors, both exogenous and endogenous. Genetic and epigenetic disorders, which emerge as a result of this influence, become the main cause of the majority of malignant neoplasias. Several different approaches were proposed to prevent these disorders, including the suppression of the activity of mutagenic factors by treatment with certain chemical compounds. Plant polyphenols are promising candidates for the development of chemopreventive drugs, as they exert the ability to regulate the metabolic activation of procarcinogens and modulate the cellular oxidative stress. In the present review, classification of plant phenolic compounds and their interactions with biological macromolecules are described, along with the molecular mechanisms of their influence on the enzymes and regulatory pathways of phase I xenobiotic metabolism, and the prevention of oxidative stress. Interactions between natural polyphenols and patient’s microbiota is also described.

Introduction. Glucocorticoids are often used in combination therapy for breast cancer as an adjuvant to increase therapeutic effects of the main cytotoxic drug and to reduce side effects of chemotherapy. However, glucocorticoids can cause serious complications and trigger tumor progression. In the last decade, it was found that side effects from glucocorticoids are mediated by an increase in REDD1 gene expression. Using this knowledge, we have developed a new chemotherapeutic strategy for blood cancers aimed at reducing adverse events from glucocorticoids. Successful experiments with a combination of glucocorticoids and REDD1 expression inhibitors on the models of blood tumors allowed us to use this regimen for the treatment of certain subtypes of breast cancer.Objective: to optimize the algorithm of breast cancer cell treatment with a combination of glucocorticoids and REDD1 expression inhibitors on the example of rapamycin.Materials and methods. We used the MCF-7 and MDA-MB-231 breast cancer cell lines. The antiproliferative activity was estimated by direct cell count; REDD1 expression was measured using western blotting and quantitative polymerase chain reaction.Results. We found that rapamycin can inhibit both baseline and glucocorticoids induced REDD1 expression in the cells of luminal and triple negative breast cancer. The drug demonstrated lower ability to inhibit the viability of breast cancer cells than that of leukemia and lymphoma cells.Conclusion. Inhibited proliferation of breast cancer cells after their incubation with rapamycin and dexamethasone, as well as the ability of rapamycin to reduce basal and glucocorticoid-induced REDD1 expression in breast cancer cells suggest the importance of studies analyzing the impact of combinations that include glucocorticoids and REDD1 expression inhibitors from the class of PI3K/Akt/mTOR signaling pathway modulators (phosphoinositide-3-kinase/α-serine-threonine kinase/mammalian rapamycin target) on breast cancer cells.

Introduction. Current chemotherapy of breast cancer has a wide range of disadvantages, in particular, the development of therapy-related infections and hormonal imbalance. Combination of main cytostatic with glucocorticoids allows to broaden its therapeutic interval and to decrease the total toxicity of the treatment. However, long-term treatment with glucocorticoids leads to the development of severe side effects via activation of multiple molecular mechanisms. Thus, glucocorticoids activate prosurvival mTOR-dependent autophagy. Therefore, the evaluation of PI3K (phosphoinositide 3-kinases) / Akt (protein kinase B) / mTOR (mammalian target of rapamycin) inhibitors as adjuvants for breast cancer therapy is important for optimization of treatment protocol.Aim. Analysis of the effects of PI3K/Akt/mTOR inhibitors, rapamycin, wortmannin and LY-294002 in combination with glucocorticoids in breast cancer cell lines of different subtypes.Materials and methods. We demonstrated the inhibition of PI3K/Akt/mTOR signaling and the autophagy induction after the treatment of breast cancer cells with rapamycin, wortmannin and LY-294002 by Western blotting analysis of Beclin-1, phospho-Beclin-1 (Ser93 and Ser30).Conclusion. PI3K/Akt/mTOR inhibitors in combination with Dexamethasone cooperatively inhibited mTOR signaling and activated autophagy in breast cancer cells in vitro.

Nanomaterials become more widespread in the different areas of human life, forming the new technosphere philosophy, in particular, new approaches for development and usage of these materials in everyday life, manufacture, medicine etc.The physicochemical characteristics of nanomaterials differ significantly from the corresponding indicators of aggregate materials and at least some of them are highly reactive and / or highly catalytic. This suggests their aggressiveness towards biological systems, including involvement in carcinogenesis. The review considers the areas of use of modern nanomaterials, with special attention paid to the description of medicine production using nanotechnologies, an analysis of the mechanisms of action of a number of nanomaterials already recognized as carcinogenic, and also presents the available experimental and mechanistic data obtained from the study of the carcinogenic / procarcinogenic effects of various groups of nanomaterials currently not classified as carcinogenic to humans.Preparing the review, information bases of biomedical literature were analysed: Scopus (307), PubMed (461), Web of Science (268), eLibrary.ru (190) were used. To obtain full-text documents, the electronic resources of PubMed Central (PMC), Science Direct, Research Gate, Sci-Hub and eLibrary.ru databases were used.

The purpose of the study was to analyze the ability of five antitumor drugs from the pharmaceutical group of protein kinase inhibitors (gefitinib, imatinib, pazopanib, ponatinib and enzastaurin) to reactivate the expression of the epigenetically silenced GFP in HeLa TI cells, and to estimate the effect of epigenetically active drugs on: 1) acetylation and methylation of histones H3 and H4; 2) integral DNA methylation; 3) activity of HAT and HDAC1 enzymes; 4) expression levels of the genes encoding epigenetic regulation enzymes (DNMT1, DNMT3A, DNMT3B; SIRT1, HDAC1; SETD1A, SETD1B, SUV420H1, SUV420H2, SUV39H1, SUV39H2). Material and Methods. The epigenetic activity of antitumor drugs was determined using the HeLa TI test system, a population of HeLa cells with the retroviral vector containing the epigenetically silenced GFP. The level of integral DNA methylation was analyzed using MspI/HpaII methyl-sensitive restriction analysis. Histone modifications were analyzed by Western blotting with antibodies to acetylated and methylated histones H3 and H4. The total activity of HAT enzymes was analyzed using Histone Acetyltransferase Activity Assay Kit. Expression of the epigenetic enzyme genes was analyzed using real-time quantitative RT-PCR. Results. It was shown that only the enzyme inhibitor Cβ protein kinase enzastaurin had the ability to reactivate the expression of epigenetically silenced GFP in the HeLa TI cells. We showed that under the action of enzastaurin, the level of integral DNA methylation and expression of DNMT3A and DNMT3B DNA methyltransferase genes decreased. It was also found that enzastaurin reduced the expression levels of histone deacetylases HDAC1 and SIRT1, but did not affect the activity and expression levels of histone acetylases, the level of histone methylation (H3K4me3, H3K9me3, H3K27me3, H4K20me3), and the level of expression of the histone methyltransferases (SUV39H1, SUV39H2, SUV420H1, SUV420H2, SETD1A и SETD1B). Conclusion. The data obtained are important for clarifying the mechanisms of action of 5 protein kinase inhibitors, in particular with respect to enzastaurin, the protein kinase Cβ inhibitor, for which the ability to reactivate epigenetically silent genes due to the effect on DNA methylation and histone acetylation was demonstrated.

Background. Curaxin CBL0137 is a novel non-genotoxic compound with anti-cancer activity based on CBL0137 ability of non-covalent interaction with DNA causing histone chaperone FACT relocation. Anti-cancer activity of this drug was demonstrated previously on the wide panel of solid cancer models in vitro and in vivo.Objectives. Estimation of anticancer effects of CBL0137 on the acute myeloblastic leukemia cells (THP-1) and acute lymphoblastic leukemia (CCRF-CEM).Materials and methods. CBL0137 cytotoxicity was analyzed using the MTT test, the effects on the cell cycle and the induction of apoptosis was assessed by flow cytometry, the activity of signaling pathways in cells treated with CBL0137 was determined by real-time polymerase chain reaction.Results. Cell treatment with CBL0137 led to cell cycle arrest and apoptosis induction. In the study of CBL0137 effect on target gene clusters of 10 signal transduction pathways involved in the pathogenesis of acute leukemia we have showed that CBL0137 inhibited the expression of down-stream genes of WNT and Hedgehog signaling in both cell lines. In THP-1 cells we also observed the inhibition of the expression of PPARγ target and hypoxia-activated genes. In CCRF-CEM cells CBL0137 also induced the expression of Notch signaling target genes.Conclusion. The antitumor activity of CBL0137 was demonstrated on acute leukemia cell cultures, the drug possesses cytotoxicity, causes cell cycle arrest and activation of apoptosis. Significant changes in the expression of efferent gene clusters of several signaling pathways were observed in the cells treated with CBL0137.

Objectives: to provide a rationale for existing approaches for the evaluation of chemoresistance of ovarian cancer in vitro, to perform a comparative analysis of the methods and to assess the perspectives of their further application.Materials and methods. For the review preparation, we analyzed articles on experimental testing of ovarian cancer resistance to chemotherapeutic agents, available at biomedical literature databases SciVerse Scopus (158), PubMed (323), Web of Science (285), RSCI (64). The review cited 37 recent publications, 12 of them being published over the past three years, and 16 articles being referred as pioneer publications on techniques previously and used today.Results. Peculiarities of the main methods for assessing the resistance and sensitivity of a cancer to various chemotherapeutic drugs using primary cultures of tumor cells obtained from biopsy or surgical material are analyzed. Proliferative and metabolic activities as well as the level of cell death were considered as the main evaluated characteristics of tumor cells. The methodological features of the described methods are discussed, as well as the prospects for their further application.Conclusion. Predictive detection of chemoresistance of ovarian cancer is based on testing the viability of tumor cells in the presence of a chemotherapeutic drug. The results of studies of the key mechanisms of chemoresistance development in tumor cells provide the rationale for improving in vitro testing.

Objective. Review of the modern methodological approaches for testing and studying the epigenetic activity of xenobiotics.Materials and methods. In preparing the review, we used information databases of biomedical literature SciVerse Scopus (538), PubMed (746), Web of Science (625), RSCI (45). To obtain full-text documents, electronic resources of PubMed Central (PMC), Research Gate, RSCI, CyberLeninka were used. In the text of the review, 87 modern publications (2010–2019) were cited, as well as 17 earlier articles published by the founders of the methods, which are used today.Results. In the review, current data on epigenetic regulation for gene expression at the level of DNA methylation and histone modification are discussed, in vitro model systems and model organisms are described, and modern methods for screening of epigenetically active xenobiotics are presented.Conclusion. Modern data concerning the mechanisms of epigenetic regulation of gene expression, the usage of existing model systems and model organisms, as well as the application of various methodological approaches and techniques, allow extensive screening of xenobiotics (including drugs and compounds synthesized for national economic tasks) for epigenetic activity. The identification of epigenetically active compounds is important in terms of improving the prevention and treatment of a number of diseases and, in particular, malignant neoplasms.

Resveratrol, genistein and quercetin from the group of polyphenols from secondary plant metabolites reveal cancer preventive and antivirus effects realized via their pleiotropic influence on the different macromolecules in cells. These compounds can interact with DNA without the formation of covalent bonds. This process is usually followed by changes in spatial, physical-chemical and structural DNA characteristics that can result in disfunction of DNA metabolism enzymes and chromatin destabilization. Similar effects were described for anticancer drug Curaxine CBL0137 in association with activation of interferon-α signaling. We demonstrated dose-dependent stimulating effects of resveratrol, genistein and quercetin on interferon-α signaling using HeLa cells expressed mCherry protein with interferon-stimulated response elements (ISRE) in promoter. Furthermore, it was shown by live-cell fluorescent microscopy in HT1080 cells with mCherry-labeled histone H1.5 that described polyphenols induced the redistribution of this linker histone in cell nuclei. The data obtained suggest an existence of DNA-dependent mechanism of anticancer effects of plant polyphenols and a need for further study of crosslinks between the polyphenols’ influence on chromatin structure and the changes in genome function, in particular, induction of interferon- interferon-α signaling.

The presented review is devoted to the analysis of molecular mechanisms of action for different natural DNA-tropic compounds with established tumor preventive activity. Here we present their cancer preventive effects observed in vivo, mechanisms of DNA binding, influence on epigenetic regulation and “housekeeping” protein function. Additionally, the influence of these compounds on DNA helix parameters is discussed that should impact on epigenetic regulation of gene expression and formation of topologically associated domains.

The mechanisms of anticancerogenic effects of flavanoids and isocyanates from the plants widely consumed in the midland belt of Russia were reviewed. Data of studies both in vitro and in vivo were analyzed. Special attention was paid to inhibition of targets responsible for carcinogen metabolic activation, carcinogenesis promotion and tumor progression as well as neoangiogenesis. Besides that the antioxidant properties of flavonoids and their effects on cell cycle regulation, apoptosis initiation and cell mobility were considered.

Trabectedin (ET-743, Yondelis) is an alkaloid that was originally isolated from the Caribbean Sea squirt, Ecteinascidia turbinata and is now produced synthetically. Its chemical structure consists in three fused tetrahydroisoquinoline rings. Two of them, A and B, binds covalently to guanine residues in the minor groove of the DNA double helix to bend the molecule toward the major groove and the third ring C protrudes from the DNA duplex, apparently allowing interactions with several nuclear proteins. Binding to the minor groove of DNA, trabectedin trigger a cascade of events that interfere with several transcription factors, DNA binding proteins, and DNA repair pathways in particular nucleotide excision repair. It acts both as a DNA-alkylating drug and topoisomerase poison. Trabectedin-DNA adduct traps the nucleotide excision repair proteins repairing the DNA damage in transcribing genes and induces DNA strand breaks. Cells deficient in homologous recombination pathway which repairs these double-strand breaks show increased sensitivity to trabectedin. The most sensitive of them were myxoid liposarcomas. Trabectedin is also effective in chemotherapy-experienced patients with advanced, recurrent liposarcoma or leiomyosarcoma as well as in women with ovarian cancer and breast cancer with BRCAness phenotype. Besides of tumor cells Trabectedin inhibits inflammatory cells by affecting directly monocytes and tumorassociated macrophages and indirectly by inhibiting production of inflammatory mediators, the cytokines and chemokines. It inhibits also the MDR-1 gene, which is responsible for the resistance of cancer cells to chemotherapeutic agents and strikes tumor angiogenesis.