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Previously, we found a significant increase in TRAIL (TNFα-related apoptosis-inducing ligand) resistance of acute myeloid leukemia (AML) cells in multicellular aggregates in vitro that simulate the location of leukemia cells in the bone marrow. In this study, we tried to assess whether the increased resistance of the AML cells to the cytotoxic effect of TRAIL in multicellular aggregates in vitro can be associated with the launch of mechanisms mediated by cell differentiation or the acquisition of a pro-inflammatory phenotype. The phenotype of THP-1 cells in aggregated and disaggregated cultures was studied in comparison with the phenotype of a disaggregated THP-1 cell culture exposed to factors that induce monocyte-like differentiation or pro-inflammatory phenotype. It was found that an increase in the TRAIL resistance of the THP-1 cells in the aggregated culture was accompanied by the appearance of signs characteristic of monocyte-like differentiation and a pro-inflammatory phenotype. The results are of interest for developing approaches for suppressing TRAIL resistance of AML cells in human bone marrow.

Antibiotic resistance of bacteria is a topical problem on a global scale. Sometimes vigorous human activity leads to an increase in the number of bacteria carrying resistance genes in the environment. Antimicrobial peptides (AMPs) and similar compounds are potential candidates for combating antibiotic-resistant bacteria. Previously, we proposed and successfully tested on Thermus thermophilus a new mechanism of AMP action. This mechanism of directed coaggregation is based on the interaction of a peptide capable of forming fibrils with a target protein. In this work, we discuss the criteria for choosing a target for the targeted action of AMP, describe the features of the "parental" S1 ribosomal proteins T. thermophilus and Escherichia coli and the studied peptides using bioinformatic analysis methods, assess the antimicrobial effect of the synthesized peptides on a model organism of E. coli and cytotoxicity on cells of human fibroblasts. The obtained results will be important for the creation of new AMPs for pathogenic organisms.Antibiotikorezistentnost' bakteriĭ iavliaetsia zlobodnevnoĭ problemoĭ mirovogo masshtaba. Podchas aktivnaia chelovecheskaia deiatel'nost' privodit k uvelicheniiu predstavlennosti v okruzhaiushcheĭ srede bakteriĭ, ustoĭchivykh k deĭstviiu antibiotikov. Antimikrobnye peptidy (AMP) iavliaiutsia potentsial'nymi lekarstvennymi kandidatami dlia bor'by s takimi mikroorganizmami. Ranee nami byl predlozhen i uspeshno aprobirovan na primere Thermus thermophilus novyĭ mekhanizm deĭstviia AMP, osnovannyĭ na napravlennoĭ koagregatsii (vzaimodeĭstvii peptida, sposobnogo formirovat' fibrilly s belkom-mishen'iu). V nastoiashcheĭ rabote rassmotreny kriterii vybora misheni dlia napravlennogo deĭstviia AMP, opisany osobennosti “roditel'skikh” S1 ribosomnykh belkov Thermus thermophilus i Escherichia coli i issleduemykh peptidov s primeneniem metodov bioinformaticheskogo analiza, provedena otsenka antimikrobnogo deĭstviia sintezirovannykh peptidov na model'nom organizme Escherichia coli i tsitotoksichnosti na kletkakh fibroblastov cheloveka.

The combined effect of melatonin and cytarabin at low concentration on the cells of acute promyelocytic leukemia HL-60 was studied. It has been shown that the combined effect of these substances led to a decrease in the number of cells by 70% and the mitotic activity index by 75%. It was found that the combined effect of melatonin and cytarabin also contributed to a decrease in the expression of mitochondrial proteins. It has been demonstrated that the combined use of melatonin with low concentration of cytarabin (2 nM) reduced the expression of the voltage-dependent anion channel (VDAC1). Melatonin in combination with cytarabin similarly affected the expression of translocator protein (TSPO) and antiapoptotic protein Bcl-2. The synergistic effect of melatonin in the combined action with cytarabin has been revealed, which provides an increase in the effectiveness of its antitumor action.

—The resistance of leukemic cells to the action of chemotherapeutic drugs is the main reason for insufficient efficacy in the treatment of acute myeloid leukemia. Microenvironmental factors play one of the key roles in the formation of the phenotype of drug resistance of leukemic cells. The elucidation of the nature of drug resistance mediated by the conditions of the microenvironment is important for the identification of new pharmacological targets for conservative directed therapy. We conducted a study of the role of differentiation in the macrophage direction in increasing the drug resistance of acute myeloid leukemia cells in multicellular aggregates. It was shown that maturation does not occur in the macrophage direction in multicellular aggregates. These data indicate that other mechanisms contribute to an increased drug resistance of acute myeloid leukemia cells in multicellular aggregates.

Various amyloid aggregates, in particular, aggregates of amyloid β-proteins, demonstrate in vitro and in vivo cytotoxic effects associated with impairment of cell adhesion. We investigated the effect of amyloid aggregates of smooth-muscle titin on smooth-muscle-cell cultures. The aggregates were shown to impair cell adhesion, which was accompanied by disorganization of the actin cytoskeleton, formation of filopodia, lamellipodia, and stress fibers. Cells died after a 72-h contact with the amyloid aggregates. To understand the causes of impairment, we studied the effect of the microtopology of a titin-amyloid-aggregate-coated surface on fibroblast adhesion by atomic force microscopy. The calculated surface roughness values varied from 2.7 to 4.9 nm, which can be a cause of highly antiadhesive properties of this surface. As all amyloids have the similar structure and properties, it is quite likely that the antiadhesive effect is also intrinsic to amyloid aggregates of other proteins. These results are important for understanding the mechanisms of the negative effect of amyloids on cell adhesion.

Melatonin (N-acetyl-5-methoxytryptamine MEL) is an indolamine that has antioxidant, anti-inflammatory and anti-tumor properties. Moreover, MEL is capable of exhibiting both anti-apoptotic and pro-apoptotic effects. In the normal cells, MEL possesses antioxidant property and has an anti-apoptotic effect, while in the cancer cells it has pro-apoptotic action. We investigated the combined effect of MEL and navitoclax (ABT-737), which promotes cell death, on the activation of proliferation in acute promyelocytic leukemia on a cell model HL-60. The combined effect of these compounds leads to a reduction of the index of mitotic activity. The alterations in the level of anti- and pro-apoptotic proteins such as BclxL, Bclw, Mcl-1, and BAX, membrane potential, Ca2+ retention capacity, and ROS production under the combined action of MEL and ABT-737 were performed. We obtained that MEL in combination with ABT-737 decreased Ca2+ capacity, dropped membrane potential, increased ROS production, suppressed the expression of anti-apoptotic proteins such as BclxL, Bclw, and Mcl-1, and enhanced the expression of pro-apoptotic BAX. Since, MEL modulates autophagy and endoplasmic reticulum (ER) stress in cancer cells, the combined effect of MEL and ABT-737 on the expression of ER stress and autophagy markers was checked. The combined effect of MEL and ABT-737 (0.2 &mu, M) increased the expression of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), leading to a decrease in the level of binding immunoglobulin protein (BIP) followed by an increase in the level of C/EBP homologous protein (CHOP). In this condition, the expression of ERO1 decreased, which could lead to a decrease in the level of protein disulfide isomerase (PDI). The obtained data suggested that melatonin has potential usefulness in the treatment of cancer, where it is able to modulate ER stress, autophagy and apoptosis.

We have shown that hydroxycobalamin (vitamin B12b) increases the toxicity of diethyldithiocarbamate (DDC) to tumor cells by catalyzing the formation of disulfiram (DSF) oxi-derivatives. The purpose of this study was to elucidate the mechanism of tumor cell death induced by the combination DDC + B12b. It was found that cell death induced by DDC + B12b differed from apoptosis, autophagy, and necrosis. During the initiation of cell death, numerous vacuoles formed from ER cisterns in the cytoplasm, and cell death was partially suppressed by the inhibitors of protein synthesis and folding, the IP3 receptor inhibitor as well as by thiols. At this time, a short-term rise in the expression of ER-stress markers BiP and PERK with a steady increase in the expression of CHOP were detected. After the vacuolization of the cytoplasm, functional disorders of mitochondria and an increase in the generation of superoxide anion in them occurred. Taken together, the results obtained indicate that DDC and B12b used in combination exert a synergistic toxic effect on tumor cells by causing severe ER stress, extensive ER vacuolization, and inhibition of apoptosis, which ultimately leads to the induction of paraptosis-like cell death.

Melatonin is produced by the pineal gland. It can be regarded as an anticancer agent and used for combined therapy, owing to its oncostatic, antioxidant, and immunoregulatory activities. Retinoic acid is widely used for the treatment of acute promyelocytic leukemia, however, it has adverse effects on the human organism. We investigated the effect of melatonin and reduced concentrations of retinoic acid on the activation of proliferation in acute promyelocytic leukemiaon a cell model HL-60. The combined effect of these compounds leads to a reduction in the number of cells by 70% and the index of mitotic activity by 64%. Combined treatment with melatonin and retinoic acid decreased the expression of the Bcl-2. The mitochondrial isoform VDAC1 can be a target in the treatment of different tumors. The combined effect of and retinoic acid at a low concentration (10 nM) decreased VDAC1 expression. Melatonin in combination with retinoic acid produced a similar effect on the expression of the translocator protein. The coprecipitation of VDAC with 2&prime, 3&prime, cyclonucleotide-3&prime, phosphodiesterase implies a possible role of its in cancer development. The combined effect of retinoic acid and melatonin decreased the activity of the electron transport chain complexes. The changes in the activation of proliferation in HL-60 cells, the mitotic index, and Bcl-2 expression under combined effect of retinoic acid (10 nM) with melatonin (1 mM) are similar to changes that are induced by 1 &mu, M retinoic acid. Our results suggest that MEL is able to improve the action the other chemotherapeutic agent.