Advances in Molecular OncologyAdvances in Molecular OncologyУспехи молекулярной онкологии2313-805X2413-3787Publishing House ABV Press73010.17650/2313-805X-2024-11-4-66-79RESEARCH ARTICLESЭКСПЕРИМЕНТАЛЬНЫЕ СТАТЬИMolecular mechanisms of action of curaxin CBL0137 on breast cancer cells in vitroМолекулярные механизмы действия кураксина CBL0137 на клетки рака молочной железы in vitrohttps://orcid.org/0000-0002-7301-605XPopovaV. G.ПоповаВ. Г.
Russian Federation

24 Kashirskoe Shosse, Moscow 115522

6 Miklukho-Maklayа St., Moscow 117198

115522 Москва, Каширское шоссе, 24

117198 Москва, ул. Миклухо-Маклая, 6

https://orcid.org/0000-0001-6388-1624LylovaЕ. S.ЛыловаЕ. С.
Russian Federation

24 Kashirskoe Shosse, Moscow 115522

115522 Москва, Каширское шоссе, 24

https://orcid.org/0000-0002-0963-3432BukinaA. Yu.БукинаА. Ю.
Russian Federation

24 Kashirskoe Shosse, Moscow 115522

6 Miklukho-Maklayа St., Moscow 117198

78 Vernadskogo Prospekt, Moscow 119454

115522 Москва, Каширское шоссе, 24

117198 Москва, ул. Миклухо-Маклая, 6

119454 Москва, пр-кт Вернадского, 78

https://orcid.org/0009-0008-7714-114XZiminK. A.ЗиминК. А.
Russian Federation

Bld. 6, 1 Ostrovityanova St., Moscow 117513

117513 Москва, ул. Островитянова, 1, стр. 6

https://orcid.org/0009-0008-1533-5184KhirinM. K.ХиринМ. К.
Russian Federation

Bld. 6, 1 Ostrovityanova St., Moscow 117513

117513 Москва, ул. Островитянова, 1, стр. 6

https://orcid.org/0000-0003-3318-9391ZhidkovaЕ. М.ЖидковаЕ. М.
Russian Federation

24 Kashirskoe Shosse, Moscow 115522

115522 Москва, Каширское шоссе, 24

https://orcid.org/0000-0003-1274-4667TrapeznikovaЕ. S.ТрапезниковаЕ. С.
Russian Federation

24 Kashirskoe Shosse, Moscow 115522

78 Vernadskogo Prospekt, Moscow 119454

115522 Москва, Каширское шоссе, 24

119991 Москва, ул. Трубецкая, 8, стр. 2

https://orcid.org/0000-0002-9710-8178YakubovskayaM. G.ЯкубовскаяМ. Г.
Russian Federation

24 Kashirskoe Shosse, Moscow 115522

6 Miklukho-Maklayа St., Moscow 117198

115522 Москва, Каширское шоссе, 24

117198 Москва, ул. Миклухо-Маклая, 6

https://orcid.org/0000-0003-0896-2952MaksimovaV. P.МаксимоваВ. П.
Russian Federation

24 Kashirskoe Shosse, Moscow 115522

115522 Москва, Каширское шоссе, 24

https://orcid.org/0000-0002-8599-6833KirsanovК. I.КирсановК. И.
Russian Federation

Kirill Igorevich Kirsanov

24 Kashirskoe Shosse, Moscow 115522

6 Miklukho-Maklayа St., Moscow 117198

Bld. 2, 8 Trubetskaya St., Moscow 119991

Кирилл Игоревич Кирсанов

115522 Москва, Каширское шоссе, 24

117198 Москва, ул. Миклухо-Маклая, 6

kkirsanov85@yandex.ruN.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of RussiaФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава РоссииPeoples’ Friendship University of RussiaФГАОУ ВО «Российский университет дружбы народов»MIREA – Russian Technological UniversityФГБУ ВО «МИРЭА – Российский технологический университет»Pirogov Russian National Research Medical University, Ministry of Health of RussiaФГАОУ ВО «Российский национальный исследовательский медицинский университет им. Н.И. Пирогова» Минздрава РоссииSechenov First Moscow State Medical University, Ministry of Health of RussiaФГАОУ ВО Первый Московский государственный медицинский университет им. И.М. Сеченова Минздрава России (Сеченовский Университет)Sechenov First Moscow State Medical University, Ministry of Health of Russia1512202411466791012202410122024Copyright ©; 2024, Popova V.G., Lylova Е.S., Bukina A.Y., Zimin K.A., Khirin M.K., Zhidkova Е.М., Trapeznikova Е.S., Yakubovskaya M.G., Maksimova V.P., Kirsanov К.I.Copyright ©; 2024, Попова В.Г., Лылова Е.С., Букина А.Ю., Зимин К.А., Хирин М.К., Жидкова Е.М., Трапезникова Е.С., Якубовская М.Г., Максимова В.П., Кирсанов К.И.2024Popova V.G., Lylova Е.S., Bukina A.Y., Zimin K.A., Khirin M.K., Zhidkova Е.М., Trapeznikova Е.S., Yakubovskaya M.G., Maksimova V.P., Kirsanov К.I.Попова В.Г., Лылова Е.С., Букина А.Ю., Зимин К.А., Хирин М.К., Жидкова Е.М., Трапезникова Е.С., Якубовская М.Г., Максимова В.П., Кирсанов К.И.https://creativecommons.org/licenses/by/4.0https://umo.abvpress.ru/jour/article/view/730

Introduction. Breast cancer (BC) represents a group of malignant neoplasms with various molecular profiles, which are characterized by aberrations in the mechanisms of epigenetic transcription regulation. One of these disruptions associated with a worse prognosis is the overexpression of the BET protein family, responsible for the interaction of transcription factors with histone-rich acetylated regions. Previously, for the multitargeted epigenetically active agent curaxin CBL0137 (CBL), we have shown the ability to inhibit the expression of BRD2, BRD3, BRD4 proteins in HeLa TI cells and BRD3, BRD4 proteins in BC cells.Aim. To analyze the molecular mechanisms of CBL0137 action on BC cells in vitro, including: 1) assessment of cytotoxicity, 2) analysis of the effect on the cell cycle, 3) assessment of the ability to trigger apoptosis, 4) cause DNA damage, and 5) analyze the effect on the expression of genes involved in proliferation, apoptosis and repair processes.Materials and methods. The cytotoxicity of CBL on BC cells (MCF7, MDA-MB-231, SKBR3) was assessed using the MTT assay. The effect of the agent on the cell cycle and activation of apoptosis was analyzed by flow cytometry. Analysis of DNA damage under the action of CBL was performed using the comet assay. Changes in the expression of genes associated with proliferation, repair and apoptosis were evaluated using real-time polymerase chain reaction.Results. The half maximal inhibitory concentration (IC50) on BC cells under the action of CBL0137 were 1 μM at 72-hour exposure, 14–25 μM at 24-hour. Curaxin CBL (0.5 and 1 μM) caused G2/M cell cycle arrest, and also triggered apoptosis in all cell lines. Under the action of 1 μM CBL, an increase in the degree of DNA damage in MCF7 and SKBR3 cells was recorded, and under the action of both concentrations in MDA-MB-231 cells. The gene expression profile involved in proliferation also corresponded to the arrest in the G2/M phase of the cell cycle. Also, under the action of CBL, the activation of p53-dependent repair genes occurred. An increase in the expression of pro-apoptotic and a decrease in anti-apoptotic genes was shown.Conclusion. Curaxin CBL0137 showed differential effects on molecular processes in BC cells. We have identified a cytostatic effect of the compound, confirmed at various molecular levels. The data obtained indicate the ability of CBL0137 to inhibit tumor processes in BC cells, which makes it a potentially interesting agent for combination therapy.

Введение. Рак молочной железы (РМЖ) – злокачественные новообразования с различным молекулярным профилем, для которых характерны аберрации в механизмах эпигенетической регуляции транскрипции. Одним из таких нарушений, ассоциированных с неблагоприятным прогнозом, является гиперэкспрессия белков семейства BET, ответственных за взаимодействие транскрипционных факторов и областей, богатых ацетилированными гистонами. Ранее мы выявили способность мультитаргетного эпигенетически активного агента кураксина CBL0137 (CBL) ингибировать экспрессию белков BRD2, BRD3, BRD4 в клетках HeLa TI и белков BRD3, BRD4 в клетках РМЖ.Цель исследования – анализ молекулярных механизмов действия CBL на клетки РМЖ in vitro, включая оценку: 1) его цитотоксичности, 2) влияния на клеточный цикл, 3) способности запускать апоптоз, 4) способности вызывать повреждения ДНК, 5) воздействия на экспрессию генов, вовлеченных в процессы пролиферации, апоптоза и репарации.Материалы и методы. Цитотоксичность CBL в отношении клеток РМЖ (MCF7, MDA-MB-231, SKBR3) оценивали с помощью МТТ-теста. Влияние агента на клеточный цикл и активацию апоптоза анализировали методом проточной цитометрии. Для анализа повреждения ДНК при действии CBL использовали метод ДНК-комет. Изменение экспрессии генов, ассоциированных с пролиферацией, репарацией и апоптозом, оценивали с помощью полимеразной цепной реакции в реальном времени.Результаты. Концентрации полумаксимального ингибирования (IC50) на клетках РМЖ при действии CBL0137 составили 1 мкМ при 72-часовой экспозиции, 14–25 мкМ – при 24-часовой. кураксин CBL (в концентрациях 0,5 и 1 мкМ) вызывал арест клеточного цикла G2/M, а также запускал апоптоз во всех клеточных линиях. При действии 1 мкМ CBL зарегистрировано повышение степени повреждения ДНК в клетках MCF7 и SKBR3, при действии обеих концентраций – в клетках MDA-MB-231. профиль экспрессии генов, вовлеченных в пролиферацию, также отвечал остановке в G2/M-фазе клеточного цикла. Также при действии CBL происходила активация р53-зависимых генов репарации. Выявлено увеличение экспрессии проапоптотических генов и снижение экспрессии антиапоптотических генов.Заключение. Кураксин CBL0137 показал различное действие на молекулярные процессы в клетках РМЖ. Мы выявили цитостатический эффект этого соединения, подтвержденный на разных молекулярных уровнях. Полученные данные свидетельствуют о способности CBL ингибировать опухолевые процессы в клетках РМЖ, что делает его потенциальным агентом для комбинационной терапии.

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