Department of Pharmacy, Research Center for Marine Drugs, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai, 200127, China.
School of Pharmacy, Shanghai JiaoTong University, Shanghai, China.
Cell Oncol (Dordr). 2024 Oct;47(5):1863-1878. doi: 10.1007/s13402-024-00968-0. Epub 2024 Jul 31.
Acute erythroleukemia (AEL) is a rare and highly aggressive subtype of acute myeloid leukemia (AML) with an extremely poor prognosis when treated with available drugs. Therefore, new investigational agents capable of inducing remission are urgently required.
Bioinformatics analysis, western blot and qRT-PCR were used to reveal the potential biological mechanism of bryostatin 4 (B4), an antineoplastic macrolide derived from the marine bryozoan Bugula neritina. Then, in vivo experiments were conducted to evaluate the role of transforming growth factor (TGF)-β signaling in the progression of AEL.
Our results revealed that the proliferation of K562 cells and TF-1 cells was significantly inhibited by B4 at IC values of 37 nM and 52 nM, respectively. B4 inhibited TGF-β signaling and its downstream pathway targets, particularly the phosphorylation of Smad2, Smad3, Ras, C-RAF, ERK1/2, and MEK. B4 also played an important role in cell invasion and migration in K562 cells and TF-1 cells by reducing the protein levels of the mesenchymal cell marker vimentin. Moreover, Flow cytometry and western blot analyses demonstrated that B4 induced apoptosis and initiated G0/G1 phase arrest by modulating mitochondrial dysfunction and cyclin-dependent kinase (CDK) expression.
These findings indicated that B4 could inhibit the proliferation, migration, invasion, and TGF-β signaling pathways of AEL cells, thus suggesting that B4 possesses therapeutic potential as a treatment for AEL.
急性红白血病（AEL）是一种罕见且极具侵袭性的急性髓细胞白血病（AML）亚型，用现有药物治疗时预后极差。因此，迫切需要新的研究性药物来诱导缓解。
采用生物信息学分析、western blot 和 qRT-PCR 揭示来源于海洋苔藓虫 Bryozoan Bugula neritina 的抗肿瘤大环内酯 bryostatin 4（B4）的潜在生物学机制。然后，进行体内实验来评估转化生长因子（TGF）-β信号在 AEL 进展中的作用。
我们的结果表明，B4 在分别为 37 nM 和 52 nM 的 IC 值时可显著抑制 K562 细胞和 TF-1 细胞的增殖。B4 抑制 TGF-β信号及其下游途径靶标，特别是 Smad2、Smad3、Ras、C-RAF、ERK1/2 和 MEK 的磷酸化。B4 还通过降低间充质细胞标志物波形蛋白的蛋白水平，在 K562 细胞和 TF-1 细胞中发挥重要作用，抑制细胞侵袭和迁移。此外，流式细胞术和 western blot 分析表明，B4 通过调节线粒体功能和细胞周期蛋白依赖性激酶（CDK）表达诱导细胞凋亡并启动 G0/G1 期阻滞。
这些发现表明，B4 可抑制 AEL 细胞的增殖、迁移、侵袭和 TGF-β信号通路，表明 B4 具有作为 AEL 治疗方法的治疗潜力。
