Journal of translational medicine · 2025
Innovative evaluation of selinexor and JQ1 synergy in leukemia therapy via C-MYC inhibition.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Wang Pei-Hong, Hu Chu-Hong, Fan Jia-Qi, He Jia-Jun, Deng Ting-Fen, Xu Yan-Li, Dai Yu-Jun, Wang Shun-Qing
Аннотация
BACKGROUND: Acute myeloid leukemia (AML) remains a therapeutic challenge due to drug resistance and relapse. Selinexor, an XPO1 inhibitor, shows limited efficacy as monotherapy, necessitating combination strategies. JQ1, a BET inhibitor targeting MYC, may synergize with Selinexor to enhance antileukemic effects.
METHODS: AML cell lines, primary patient samples, and xenograft models (MLL-AF9, CDX, PDX) were treated with Selinexor and JQ1 alone or combined. Synergy was assessed via viability assays (Compusyn/SynergyFinder), apoptosis (flow cytometry/Western blot), and C-MYC suppression (qPCR/CRISPR). In vivo efficacy was evaluated by tumor burden (flow cytometry) and survival.
RESULTS: The combination demonstrated strong synergy (CI < 1, HSA > 10) across AML models, with > 80% inhibition in cell lines and primary samples. Mechanistically, it suppressed C-MYC (protein/mRNA), induced apoptosis (cleaved PARP), and arrested cell cycle. In vivo, the combination reduced leukemic burden in bone marrow, spleen, and liver, extending survival in xenografts. PDX models confirmed efficacy in primary AML cells.
CONCLUSIONS: Selinexor and JQ1 synergistically target AML by dual C-MYC inhibition, offering a promising strategy to overcome resistance. Further clinical evaluation is warranted.
METHODS: AML cell lines, primary patient samples, and xenograft models (MLL-AF9, CDX, PDX) were treated with Selinexor and JQ1 alone or combined. Synergy was assessed via viability assays (Compusyn/SynergyFinder), apoptosis (flow cytometry/Western blot), and C-MYC suppression (qPCR/CRISPR). In vivo efficacy was evaluated by tumor burden (flow cytometry) and survival.
RESULTS: The combination demonstrated strong synergy (CI < 1, HSA > 10) across AML models, with > 80% inhibition in cell lines and primary samples. Mechanistically, it suppressed C-MYC (protein/mRNA), induced apoptosis (cleaved PARP), and arrested cell cycle. In vivo, the combination reduced leukemic burden in bone marrow, spleen, and liver, extending survival in xenografts. PDX models confirmed efficacy in primary AML cells.
CONCLUSIONS: Selinexor and JQ1 synergistically target AML by dual C-MYC inhibition, offering a promising strategy to overcome resistance. Further clinical evaluation is warranted.