Drug-Related Carcinogenesis: Risk Factors and Approaches for Its Prevention

The review summarizes the data on the role of metabolic and repair systems in the mechanisms of therapy-related carcinogenesis and the effect of their polymorphism on the cancer development risk. The carcinogenic activity of different types of drugs, from the anticancer agents to analgesics, antipyretics, immunomodulators, hormones, natural remedies, and non-cancer drugs, is described. Possible approaches for the prevention of drug-related cancer induction at the initiation and promotion stages are discussed. © 2020, Pleiades Publishing, Ltd

Role of nitric oxide and endothelial NO synthase in carcinogenesis [Роль оксида азота и эндотелиальной NO-синтазы в канцерогенезе]

Introduction. Nitric oxide (NO) produced by NO synthases (NOS) is involved in the regulation of vital physiological functions. At the same time, NO and NOS are involved in events associated with the tumor process: mutagenesis, proliferation, apoptosis, angiogenesis, etc., exerting a multidirectional effect on the tumor. Objectives - analyze and summarize literature data concerning the role of NO and endothelial NOS (eNOS) in the initiation and progression of tumors, as well as in the inhibition of tumor growth. Materials and methods. In preparing the review, publications of information bases of biomedical literature were used: SciVerse Scopus (538), PubMed (1327), Web of Science (905), Russian Science Citation Index (125). Results. The molecular mechanisms of the action of NO and its derivatives on the initiation and progression of carcinogenesis have been explored. Numerous factors and conditions regulating the activity of eNOS in health and tumor growth have been analyzed. The molecular signaling pathways through which the pro-tumor effects of NO and eNOS, stimulating angiogenesis, lymphangiogenesis, are realized, including through the mobilization of stem cells, are considered. Conclusion. Nitric oxide produced by activated eNOS promotes tumor progression by increasing the proliferation of tumor cells, enhancing the action of pro-angiogenic factors, stimulating angiogenesis, lymphangiogenesis, and metastasis. Selective inhibition of increased eNOS activity may be a promising therapeutic approach aimed at reducing metastasis and tumor growth. © The Author(s), 2021

РОЛЬ НАРУШЕНИЙ СИГНАЛЬНОГО ПУТИ WNT В ПАТОГЕНЕЗЕ ЛЕЙКОЗОВ

The WNT/β-catenin signaling pathway plays an important role in the differentiation and proliferation of hematopoietic cells. In this regard, in recent years, much attention has been paid to studying the role of WNT signal transduction disorders in the pathogenesis of various malignant neoplasms of the hematopoietic system. The main mechanisms of the signaling pathology in leukemias identified to date are: hypersensitivity to the WNT ligand, epigenetic repression of WNT antagonists, overexpression of WNT ligands, degradation of β-catenin in the cytoplasm, and changes in the activity of TCF/Lef transcription factors. The corresponding molecular changes are represented by overexpression of FZD protein, hypermethylation of the SFRP, DKK, WiF, Sox, and CXXC gene promoters, overexpression of Lef1 and plakoglobin, GSK3β mutation, and β-catenin phosphorylation by BCR-ABL kinase. The present review is devoted to the systematization of these data.Сигнальный путь WNT/β-катенин играет важную роль в дифференцировке и пролиферации клеток гемопоэза. В связи с этим в последние годы значительное внимание уделяется изучению роли нарушений передачи WNT-сигнала в патогенезе различных злокачественных новообразований кроветворной системы. Основными механизмами нарушения сигнального пути, выявленными к настоящему времени в лейкозах, являются: повышение чувствительности к WNT-лиганду, эпигенетическая репрессия WNT антагонистов, гиперэкспрессия WNT-лигандов, нарушения деградации β-катенина в цитоплазме и изменение активности TCF/Lef. Соответствующие молекулярные изменения представлены гиперэкспрессией FZD, гиперметилированием промоторов генов SFRP, DKK, WiF, Sox, CXXC, гиперэкспрессией Lef1 и плактоглобина, мутацией GSK3β и фосфорилированием β-катенина киназой BCR-ABL. Систематизации этих данных посвящен представленный обзор

ДЕЙСТВИЕ ВОДНО-СПИРТОВЫХ ЭКСТРАКТОВ ПОЛЫНИ ЭСТРАГОННОЙ (ARTIMISIA DRACUNCULUS L.) И ЧЕРНОГО ФЕРМЕНТИРОВАННОГО ПАСТЕРНАКА (PASTINACA SATIVA L.) НА РОСТ И МЕТАСТАЗИРОВАНИЕ ПОДКОЖНО ПЕРЕВИВАЕМОЙ КАРЦИНОМЫ ЛЬЮИСА У МЫШЕЙ

Aim. The aim of the study was to investigate the ability of water-ethanol extracts of tarragon Artemisia dracunculus L. and black parsnip Pastinaca sativa L. to increase the body's antitumor resistance to transplanted tumor cells and have an antitumor effect on the growth and metastasis tumors in mice. Material and Methods. In the study mice with metastatic Lewis carcinoma, were used. The inhibitory effect of tarragon Artemisia dracunculus L., "Izumrud" cultivar and parsnip Pastinaca sativa L. was evaluated by inhibition of tumor growth and reduction of metastases in mice lung. Results. A comprehensive study of the chemical composition of tarragon Artimisia dracunculus L. and parsnip Pastinaca sativa L. has identified a wide range of biologically active substances capable to participate in anti-carcinogenic protection. It was shown that water-alcohol extract of tarragon Artemisia dracunculus L. did not significantly affect the growth of tumors and potent metastasizing in mice with carcinoma of Lewis. Water-alcohol extract of parsnip Pastinaca sativa L. (3.2%) demonstrated a significant inhibition of tumor growth and had a pronounced anti-metastatic effect. Conclusion. The results indicate the prospect of further study of the anticancer properties of black parsnip and its biologically active compounds.Цель исследования - изучение способности полыни эстрагонной (Artemisia dracunculus L., сорт «Изумруд») и корнеплодов черного пастернака (Pastinaca sativa L.) повышать противоопухолевую резистентность организма к трансплантируемым опухолевым клеткам и оказывать противоопухолевое действие на рост перевиваемых метастазирующих опухолей у мышей. При проведении комплексного исследования химического состава полыни эстрагонной (Artimisia dracunculus L.) и черного ферментированного пастернака (Pastinaca sativa L.) выявлен широкий спектр биологически активных веществ, способных участвовать в антиканцерогенной защите. Показано, что водно-спиртовой экстракт полыни значимо не влиял на рост опухолей и потенцировал метастазирование у мышей с перевиваемой карциномой Льюиса. Водно-спиртовой экстракт пастернака (3,2%) достоверно тормозил рост опухолей и оказывал выраженное антиметастатическое действие. Полученные данные свидетельствуют о перспективности дальнейшего изучения противоопухолевых свойств чёрного пастернака и биологически активных соединений, входящих в его состав

Alterations in WNT Signaling in Leukemias

The WNT/β–catenin signaling pathway plays an important role in the differentiation and proliferation of hematopoietic cells. In recent years, special attention has been paid to the role of impairments in the WNT signaling path–way in pathogenesis of malignant neoplasms of the hematopoietic system. Disorders in the WNT/β–catenin signaling in leukemias identified to date include hypersensitivity to the WNT ligands, epigenetic repression of WNT antagonists, over–expression of WNT ligands, impaired β–catenin degradation in the cytoplasm, and changes in the activity of the TCF/Lef transcription factors. At the molecular level, these impairments involve overexpression of the FZD protein, hypermethylation of the SFRP, DKK, WiF, Sox, and CXXC gene promoters, overexpression of Lef1 and plakoglobin, mutations in GSK3β, and β–catenin phosphorylation by the BCR–ABL kinase. This review is devoted to the systematization of these data. © 2018, Pleiades Publishing, Inc

Current Approaches for Personalized Therapy of Soft Tissue Sarcomas

Soft tissue sarcomas (STS) are a highly heterogeneous group of cancers of mesenchymal origin with diverse morphologies and clinical behaviors. While surgical resection is the standard treatment for primary STS, advanced and metastatic STS patients are not eligible for surgery. Systemic treatments, including standard chemotherapy and newer chemical agents, still play the most relevant role in the management of the disease. Discovery of specific genetic alterations in distinct STS subtypes allowed better understanding of mechanisms driving their pathogenesis and treatment optimization. This review focuses on the available targeted drugs or drug combinations based on genetic aberration involved in STS development including chromosomal translocations, oncogenic mutations, gene amplifications, and their perspectives in STS treatment. Furthermore, in this review, we discuss the possible use of chemotherapy sensitivity and resistance assays (CSRA) for the adjustment of treatment for individual patients. In summary, current trends in personalized management of advanced and metastatic STS are based on combination of both genetic testing and CSRA. © 2020 Kirill I. Kirsanov et al

Indolo[2,3-a]carbazoles: diversity, biological properties, application in antitumor therapy

[Figure not available: see fulltext.] This review presents the history of the discovery of indolo[2,3-a]carbazoles, lists the currently known natural compounds of this subclass, and gives the sources for their isolation. The main approaches used to obtain synthetic indolo[2,3-a]carbazoles are described, and examples of compounds from this group that are most promising because of their high antitumor activity are given. The spectrum of biological properties of natural and synthetic compounds of this subclass is highlighted. The molecular mechanisms of their antitumor action as the most significant in the context of clinical use are separately considered. Particular attention is paid to indolo[2,3-a]- carbazoles that have reached clinical trials or are already in use for the treatment of malignant neoplasms. © 2020, Springer Science+Business Media, LLC, part of Springer Nature

Methodological approaches to the determination of chemoresistance of human cancer cells to anti-cancer drugs

The purpose of the study was to analyze the existing methodological approaches to the experimental testing of resistance to chemotherapy and assess the prospects for their further application. Material and Methods. We analyzed publications regarding the experimental testing of tumor resistance to chemotherapy available in the databases, such as SciVerse Scopus (748), PubMed (1727), Web of Science (1025), RSCI (125). To obtain full-text publications, the electronic resources of Research Gate, RSCI, CyberLenink were used. Forty-two modern publications (2012–19) including 18 articles of the founders of the methods analyzed in the review were cited. Results. The review discusses the characteristics of the main methods for assessing the resistance / sensitivity of tumor cells obtained from biopsy / surgical specimens to various chemotherapy drugs in vitro in monolayer and suspension cultures, in the form of spheroids, histo and organocultures, as well as in vivo xenografts of tumors in immunodeficient mice. During testing, the proliferative and metabolic activities as well as the level of cell death were considered as the main evaluated characteristics of tumor cells. The main indicators were the intensity of DNA synthesis, the level of protein or ATP in the cell, the activity of NADH-dehydrogenases, the level of apoptosis, and the integrity of cell structures. The advantages and disadvantages of the described methods, as well as the prospects for their further application were discussed. Conclusion. Over the past half century of using the experimental testing of tumor cell resistance in order to personalize chemotherapeutic treatment, the evolution of methodological approaches was based on the increase in their safety and sensitivity through the use of fluorescent compounds. The general vector for improving experiments on the personalization of tumor chemotherapy is aimed at approximating the experimental conditions to the processes occurring in the human body. Each of these methods has its own range of predictive power and, if used properly, can provide a useful guide for treatment. © 2020, Tomsk National Research Medical Center of the Russian Academy of Sciences. All rights reserved

The long winding road to the safer glucocorticoid receptor (GR) targeting therapies

Glucocorticoids (Gcs) are widely used to treat inflammatory diseases and hematological malignancies, and despite the introduction of novel anti-inflammatory and anti-cancer biologics, the use of inexpensive and effective Gcs is expected to grow. Unfortunately, chronic treatment with Gcs results in multiple atrophic and metabolic side effects. Thus, the search for safer glucocorticoid receptor (GR)-targeted therapies that preserve therapeutic potential of Gcs but result in fewer adverse effects remains highly relevant. Development of selective GR agonists/modulators (SEGRAM) with reduced side effects, based on the concept of dissociation of GR transactivation and transrepression functions, resulted in limited success, and currently focus has shifted towards partial GR agonists. Additional approach is the identification and inhibition of genes associated with Gcs specific side effects. Others and we recently identified GR target genes REDD1 and FKBP51 as key mediators of Gcs-induced atrophy, and selected and validated candidate molecules for REDD1 blockage including PI3K/Akt/ mTOR inhibitors. In this review, we summarized classic and contemporary approaches to safer GR-mediated therapies including unique concept of Gcs combination with REDD1 inhibitors. We discussed protective effects of REDD1 inhibitors against Gcs–induced atrophy in skin and bone and underlined the translational potential of this combination for further development of safer and effective Gcs-based therapies. Copyright: © 2022 Lesovaya et al

Противоопухолевая активность кураксина CBL0137 на моделях острых лейкозов in vitro

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.Введение. Кураксин CBL0137 - новое негенотоксичное соединение, обладающее противоопухолевой активностью, в основе которой лежит способность препарата нековалентно взаимодействовать с ДНК, вызывая транслокацию гистонового шаперона FACT в хроматиновую фракцию. Ранее противоопухолевая активность этого агента была продемонстрирована относительно широкого спектра солидных опухолей in vitro и in vivo.Цель исследования - изучение противоопухолевой активности CBL0137 в отношении клеток острого миелобластного лейкоза (THP-1) и острого лимфобластного лейкоза (CCRF-CEM) in vitro.Материалы и методы. Для определения цитотоксичности CBL0137 использовали МТТ-тест, влияние на клеточный цикл и индукцию апоптоза оценивали с помощью проточной цитофлуориметрии, активность функционирования сигнальных путей при действии на клетки CBL0137 определяли с помощью полимеразной цепной реакции в реальном времени.Результаты. Обработка клеток CBL0137 приводит к аресту клеточного цикла и активации апоптоза. При исследовании влияния CBL0137 на кластеры таргетных генов 10 сигнальных путей, вовлеченных в онкогенез острых лейкозов, его ингибирующее действие было выявлено для сигнальных путей WNT и Hedgehog в обеих клеточных линиях. В клеточной линии THP-1 также наблюдалось ингибирование эфферентных генов PPARγ и генов, активирующихся при гипоксии. В клетках CCRF-CEM при действии CBL0137, кроме того, наблюдалось усиление экспрессии всех исследованных таргетных генов сигнального пути Notch.Заключение. На культурах клеток острых лейкозов продемонстрирована противоопухолевая активность CBL0137, препарат обладает цитотоксичностью, вызывает арест клеточного цикла и активацию апоптоза. При действии CBL0137 наблюдаются значительные изменения в экспрессии кластеров эфферентных генов сразу нескольких сигнальных путей