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Breast cancer is the leading malignancy in women worldwide. To date, much is known about the molecular subtypes of these malignant neoplasms and the mechanisms of drug resistance. Significant success has been achieved in approaches to early diagnosis, which allows identifying the tumor process in the early stages of development. Recently, the study of the influence of the human body microbiota on cancer development and the effectiveness of treatment has become an actively developing field of research. This review presents an analysis of the literature data on this issue.

This review presents up-to-date information on the effects of microbiota on the individual chemotherapy sensitivity in cancer treatment. Recent studies have shown that a fine balance between the intestinal microbiota and the immune system is crucial for maintaining an efficacy of cancer chemotherapy. A number of antitumor drugs have complex mechanisms of action involving not only direct effects but also the activity of the intestinal microbiota and the immune system. A unique combination of these factors contributes to the individual chemotherapy sensitivity.

Aim: To investigate the mechanisms of cytotoxic activity and pro-/antioxidant effect of lactoferrin on hormone receptor-positive and receptor-negative breast cancer cells in vitro., Materials and Methods: The study was performed on receptor-positive (MCF-7, T47D) and receptor-negative (MDA-MB-231, MDA-MB-468) human breast cancer cell lines. Immunocytochemical staining, flow cytometry, low-temperature electron paramagnetic resonance, and the Comet assay were used., Results: Upon treatment with lactoferrin, the increased levels of reactive oxygen species (ROS) (p < 0.05), NO generation rate by inducible NO-synthase (p < 0.05) and the level of "free" iron (p < 0.05) were observed. Moreover, the effects of lactoferrin were more pronounced in receptor-negative MDA-MB-231 and MDA-MB-468 cells. These changes resulted in increased expression of proapoptotic Bax protein (p < 0.05), reduced expression of the antiapoptotic Bcl-2 protein (p < 0.05) and level of not-oxidized mitochondrial cardiolipin (1.4-1.7-fold, p < 0.05). This, in turn, caused an increase in the percentage of apoptotic cells (by 14-24%, p < 0.05). Cytotoxic effects of lactoferrin were accompanied by an increase in the percentage of DNA in the comet tail and blocking cell cycle at G2/M phase, especially in receptor-negative cell lines., Conclusion: The study showed that exogenous lactoferrin causes a violation of an antioxidant balance by increasing the level of ROS, "free" iron and NO generation rate, resalting in the blocking of cell cycle at G2/M-phase and apoptosis of malignant cells.

Aim: To study the cytostatic and some biological effects of aminoferrocene using mice with L1210 lymphoid leukemia., Materials and Methods: Experiments were performed on BDF1 male mice (DBA/2, female × C57Bl/6, male) with transplantable L1210 lymphoid leukemia. Determination of antitumor activity of Benzyl-Fc Boron (Bn), it was injected intraperitoneally 6 times daily, starting on day 2 after L1210 leukemia cell transplantation. Doses of Bn such as 26; 260 and 2600 μg/kg were used. The determination of intracellular content of cardiolipin, thiols, reactive oxygen species (ROS) and also analysis of Annexin V positivity and mitochondrial transmembrane potential (JC-1 staining) were performed with use of flow cytometry. The levels of "free iron" complexes, transferrin active forms and the rate of NO generation were measured by EPR-specroscopy., Results: Six daily injections of Bn at a dose of 26 μg/kg resulted in an increased survival of mice with L1210 leukemia by 28% (p < 0.05). Bn led to an increase of apoptotic cells number and ROS amount in leukemia cells. Besides, Bn caused a decrease of cardiolipin and nonprotein thiol compounds content. The membrane electrochemical potential of cell mitochondria was decreased also after Bn administration. Studies using EPR-spectroscopy revealed a significant increase in a level of "free iron", content of transferrin active species and generation rate of NO by inducible NO-synthase in L1210 cells after aminoferrocene administration., Conclusion: Our data indicate that Benzyl-Fc Boron can be promising candidate for realizing a new strategy of anticancer therapy with the use of ROS-inducing agents.

Aim: To study indices of energy metabolism, content of K(+) and Mg(++) both in peripheral blood and in Walker-256 carcinosarcoma during development of resistance to doxorubicin., Methods: Resistance of Walker-256 carcinosarcoma to doxorubicin has been developed through 12 subsequent transplantations of tumor after the chemotherapy. Parental strain was inhibited by drug by 65%, while transitional resistant substrains - by 30% and 2%, respectively. Determination of biochemical indices in blood serum and homogenates of tumor tissue, level of potassium, magnesium, lactate, glucose, activities of lactate dehydrogenase and glucose-6-phosphate dehydrogenase was performed with the help of biochemical and immune-enzyme analyzer GBG ChemWell 2990 (USA) using standard kits. Polarography was used to determine indices of mitochondrial oxidative phosphorylation. Study of mitochondrial membrane potential was carried out on flow cytometer Beckman Coulter Epics XL using dye JC-1., Results: It has been determined that development of drug resistance causes the decrease of K(+), Mg(++), glucose content in blood serum and increase of these indices in tumor tissue. At the same time, gradual tumor's loss of sensitivity is characterized by decrease of glycolysis activity in it and activation of mitochondrial oxidative phosphorylation and pentose phosphate pathway of glucose degradation, which causes more intensive formation of NADPH., Conclusion: Development of drug resistance of tumor causes certain metabolic changes in organism and tumor. Further study of such changes will make possible to determine tumor and extratumor markers of resistance.

Aim: The aim of our study is to investigate the disorders of ferritin functioning in breast cancer (BC) cells of different molecular subtype., Materials and Methods: The cell lines used in the analysis include T47D, MCF-7, MDA-MB-231, MDA-MB-468, MCF-10A, and 184A1. Ferritin heavy chains (FTH) expression was studied by immunohistochemical method. "Free iron" content and superoxide dismutase (SOD) activity were determined by means of EPR spectroscopy. Reactive oxygen species (ROS) level and peculiarities of microRNA expression in studied cell lines were evaluated using flow cytometry and PCR analysis, respectively., Results: It has been demonstrated that FTH expression directly correlates with proliferative activity of cells of both luminal (r = 0.51) and basal subtypes (r = 0.25), inversely correlates with expression of steroid hormones in cells of basal subtype (ER: r = -0.46; PR: r = -0.44) and does not depend on tumorigenic activity of both subtypes of studied cells (r = 0.12 and r = 0.9). Obtained data are the evidence that cells of luminal subtype B (MCF-7 cell line) and basal subtype (MDA-MB-231 and MDA-MB-468 cell lines) with high proliferative activity contain the highest level of free iron (2.9 ± 0.19·10(16)and 3.0 ± 0.22·10(16)) that can be consequence of intensive use of this element by cells, which actively divide and grow. Along with it, in cell of lines of basal subtype MDA-MB-231 and MDA-MB-468, high level of FTH (254 ± 2.3 and 270 ± 1.9) is being detected in consequence of increase of level of free iron, ROS (11.3 ± 1.05 and 7.27 ± 0.26) and SOD (9.4 ± 0.24 and 8.5 ± 0.18) as well as decrease of expression of microRNA 200b. In contrast, cells of luminal subtype B of MCF-7 line were distinguished by high expression of microRNA 200b and low ferritin level (125 ± 2.7)., Conclusion: Obtained data demonstrate that tumor cells, which are referred to different molecular subtypes, are characterized by changes in system of support of balance of intercellular iron and certain associations of studied factors.