Том 88, № 7 (2023)

Sphingolipids are a diverse family of complex lipids, in which the determining component is sphingoid base, usually bound to a fatty acid by an amide bond. The metabolism of sphingolipids has long remained on the periphery of biochemical research. Recently, it has begun to attract more and more attention due to the diverse and often multidirectional effects of sphingolipids with a similar chemical structure. Sphingosine and ceramides (N-acylsphingosines), as well as their phosphorylated derivatives (sphingosine-1-phosphate and ceramide-1-phosphates) play the role of signaling molecules. Ceramides can cause apoptosis, regulate the stability of cell membranes and the cellular response to stress. In general, ceramides and sphingoid bases as signaling molecules slow down anabolic and accelerate catabolic reactions, suppressing cell proliferation. Phosphorylated derivatives of ceramide-1-phosphate and sphingosine-1-phosphate, on the contrary, stimulate cell proliferation and division. The significant participation of sphingolipids in the regulation of apoptosis and cell division processes makes them critically important compounds regulating tumor progression. The enzymes of sphingolipid metabolism and the receptors of the corresponding sphingolipids can be considered as targets for antitumor therapy. This review aims to highlight the main pathways of metabolism of sphingolipids in human cells, with special emphasis on the known features of their metabolism in tumor cells.

The widespread use of next-generation sequencing (NGS) technologies revealed that a significant percentage of tumors in children develop as a part of monogenic hereditary diseases. Predisposition to the development of pediatric neoplasms is characteristic of a wide range of conditions including hereditary tumor syndromes, primary immunodeficiencies, rasopathies, and phakomatosis. The mechanisms of tumor molecular pathogenesis are diverse and include disturbances in signaling cascades, defects in DNA repair, chromatin remodeling, and microRNA processing. Timely diagnosis of tumor-associated syndromes is important for the proper choice of cancer treatment, genetic counseling of families, and the development of surveillance programs. The review describes the spectrum of neoplasms characteristic of the most common syndromes and the molecular pathogenesis of these diseases.

The pharmacological value of some natural compounds makes them attractive for use in oncology. Sulfur-containing thiosulfinates found in plants of the genus Allium have long been known as compounds with various therapeutic properties, including antitumor. In recent years, the effect of thiosulfinates on various stages of carcinogenesis has been actively studied. In vitro and in vivo studies have shown that thiosulfinates inhibit the proliferation of cancer cells, as well as induce apoptosis. The purpose of this review is to summarize current data on the use of natural and synthetic thiosulfinates in cancer therapy. Antitumor mechanisms and molecular targets of these promising compounds are discussed. A significant part of the review is devoted to the consideration of a new strategy for the treatment of oncological diseases - the use of the method of directed enzyme prodrug therapy with the possibility of obtaining antitumor thiosulfinates in situ.

All types of cancer are addicted to methionine, which is known as the “Hoffman effect”. Restricting methionine inhibits the growth and proliferation of all tested types of cancer cells, while normal cells are unaffected. Methionine addiction is targeted with methioninase (METase), which has been shown to be effective and safe as a therapy for all types of cancer cells and animal cancer models, either alone or in combination with common cancer medications. Approximately six years ago, researchers developed a rMETase that may be taken orally as a supplement and has resulted in anecdotal positive results in patients with advanced cancer. Currently, there are 8 clinical studies on METase, including 2 from the 1990s and 6 more recent ones. This review focuses on the clinical studies of METase-mediated methionine restriction, specifically the oral dosage form of rMETase as a supplement alone or in combination with common chemotherapeutic agents in the treatment of patients with advanced cancer.

Aberrant methylation and acetylation of histones are characteristic changes in the system of epigenetic regulation of gene expression accompanying the process of malignant transformation of the cell. Vorinostat is the epigenetic modulator that actively used in clinical oncology practice. The antitumor activity of vorinostat is considered to be associated with only with the inhibition of histone deacetylases. The effects of this drug on histone methylation have not been sufficiently studied. Using the HeLa TI test system, which allows evaluating the integral effect of epigenetically active compounds by activating the expression of the reporter gene GFP, and knockdown of genes by small interfering RNAs, we showed that the inhibitory effect of vorinostat is directed not only at HDAC1, but also at EZH2, SUV39H1, SUV39H2, SUV420H1. Using Western blotting, the ability of vorinostat to suppress the expression of enzymes EZH2, SUV39H1/2, SUV420H1 was confirmed and, in addition, its ability to inhibit the expression of enzymes SUV420H2 and DOT1L was revealed. The data obtained expand the understanding of the epigenetic effects of vorinostat and demonstrate the need for a large-scale analysis of its activity in relation to other epigenetic enzymes. A detailed understanding of the mechanism of epigenetic action of vorinostat will contribute to its more adequate use in the treatment of tumors with an aberrant epigenetic profile.

Currently, a significant increase in the levels of circulating cell-free DNA (cfDNA) in the blood of patients is a generally recognized marker of the development of oncological diseases. Although tumor-associated cfDNA has been well studied, its biological functions remain unclear. In this work, we investigated the effect of cfDNA isolated from the blood serum of mice with B16-F10 metastatic melanoma on the properties of B16-F10 melanoma cells in vitro. It was found that the profile of cfDNA isolated form blood serum of mice with melanoma differs significantly from the cfDNA isolated from blood serum of healthy mice, and is similar concerning the abundance of oncogenes and mobile genetic elements (MGE) to the genomic DNA of B16 cells. It was shown that cfDNA of mice with melanoma penetrated into B16 cells, resulting to the increase in the abundance of oncogenes and MGE fragments, and caused the 5-fold increased mRNA level of the secreted DNase Dnase1l3 and a slight increase of the mRNA level of the Jun, Fos, Ras, and Myc oncogenes. cfDNA of healthy mice caused increasing of mRNA level of the intracellular regulatory DNase EndoG and a 4-fold increase of mRNA level of Fos and Ras oncogenes, which are well-known triggers of a large number of signal cascades, from apoptosis inhibition to increased tumor cell proliferation. Thus, it is obvious that the circulating cfDNA of tumor origin is able to penetrate into cells and, despite the fact that no changes were found in the level of viability and migration activity of tumor cells, cfDNA, even with a single exposure, can cause changes at the cellular level that increase the oncogenicity of recipient cells.

Pyridoxal-5′-phosphate (PLP), a phosphorylated form of vitamin B6, acts as a coenzyme for numerous reactions, including those changed in cancer and/or associated with the disease prognosis. Since highly reactive PLP may modify cellular proteins, it is hypothesized to be directly transferred from its donors to acceptors. Our goal is to validate the hypothesis by finding common motif(s) in a multitude of the PLP-dependent enzymes for binding the limited number of the PLP donors, namely pyridoxal kinase (PdxK), pyridox(am)in-5′-phosphate oxidase (PNPO) and the PLP-binding protein (PLPBP). Experimentally confirmed interactions between the PLP donors and acceptors reveal that PdxK and PNPO interact with the PLP acceptors of folds I and II, while PLPBP - with those of folds III and V. Aligning the sequences and 3D structures of the identified interactors of PdxK and PNPO, we have found a common motif in the PLP-dependent enzymes of folds I and II. The motif extends from the enzyme surface to the neighborhood of the PLP binding site, represented by an exposed alfa-helix, a partially buried beta-strand and residual loops. Pathogenicity of mutations in human PLP-dependent enzymes within or in the vicinity of the motif, but outside of the active sites, supports functional significance of the motif that may provide an interface for the direct transfer of PLP from the sites of its synthesis to those of the coenzyme binding. The enzyme-specific amino acid residues of the common motif may be used to develop selective inhibitors blocking PLP delivery to the PLP-dependent enzymes critical for proliferation of malignant cells.