БИОХИМИЯ, 2025, том 90, вып. 12, с. 2119–2138

УДК 577.12

Механизмы и способы преодоления приобретенной устойчивости опухолевых клеток к антагонистам Mcl‑1

© 2025 Н.В. Первушин 1,2, Б.И. Вальдес Фернандес 2, В.В. Сеничкин 2, М.А. Япрынцева 1,2, В.С. Павлов 1, Б. Животовский 1,2,3*boris.zhivotovsky@ki.se, Г.С. Копеина 1,2*lirroster@gmail.com

1 Институт молекулярной биологии имени В.А. Энгельгардта РАН, 119991 Москва, Россия

2 Московский государственный университет имени М.В. Ломоносова, факультет фундаментальной медицины, 119991 Москва, Россия

3 Институт медицины окружающей среды, Каролинский институт, 17177 Стокгольм, Швеция

Поступила в редакцию 24.08.2025
После доработки 22.10.2025
Принята к публикации 29.10.2025

DOI: 10.7868/S3034529425120156

КЛЮЧЕВЫЕ СЛОВА: лекарственная устойчивость, Mcl‑1, ВН3‑миметики, апоптоз, опухолевые клетки.

Аннотация

Приобретенная лекарственная устойчивость снижает эффективность противоопухолевой терапии и ведет к прогрессированию онкологических заболеваний. Селективное ингибирование антиапоптотических белков семейства Bcl‑2 за счет ВН3‑миметиков является перспективной стратегией лечения онкологических пациентов. На протяжении последних лет антагонисты антиапоптотического белка Mcl‑1 активно исследуются в клинических испытаниях, но, как и другие ВН3‑миметики, могут терять свою эффективность вследствие появления к ним приобретенной устойчивости. Нами было установлено, что опухолевые клетки вырабатывают устойчивость к ингибированию Mcl‑1 за счет увеличенной экспрессии генов других антиапоптотических белков – Bcl‑2 или Bcl‑xL, становясь менее Mcl‑1-зависимыми. Развитие данного типа устойчивости также сопровождается изменениями метаболизма клеток. Нами было показано, что комбинирование антагониста Mcl‑1 S63845 с различными противоопухолевыми соединениями способно вести к преодолению устойчивости злокачественных клеток к его действию.

Сноски

* Адресат для корреспонденции.

Дополнительные материалы

Приложение

Вклад авторов

Н.В. Первушин, Б. Животовский, Г.С. Копеина – концепция и руководство работой; Н.В. Первушин, Б.И. Вальдес Фернандес, В.В. Сеничкин, М.А. Япрынцева, В.С. Павлов – проведение экспериментов; Н.В. Первушин, В.В. Сеничкин, Б. Животовский, Г.С. Копеина – обсуждение результатов исследования; Н.В. Первушин – написание текста и подготовка рисунков; Б. Животовский, Г.С. Копеина – редактирование текста статьи.

Финансирование

Работа выполнена при поддержке гранта РНФ (проект № 23-74-30006). Работа в лабораториях авторов (для Животовского Б.) также поддержана Шведским (222013) и Стокгольмским (181301) онкологическими фондами.

Благодарности

Исследование выполнено в рамках государственного задания МГУ имени М.В. Ломоносова.

Конфликт интересов

Авторы заявляют об отсутствии конфликта интересов.

Соблюдение этических норм

Настоящая статья не содержит описания выполненных авторами исследований с участием людей или животных в качестве объектов.

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