Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien 970374, Taiwan; Institute of Medical Sciences, Tzu Chi University, Hualien 970374, Taiwan.
Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien 970374, Taiwan.
Biomed Pharmacother. 2024 Oct;179:117395. doi: 10.1016/j.biopha.2024.117395. Epub 2024 Sep 5.
Core binding factor acute myeloid leukemia (CBF-AML) stands out as the most common type of adult AML, characterized by specific chromosomal rearrangements involving CBF genes, particularly t(8;21). Shikonin (SHK), a naphthoquinone phytochemical widely employed as a food colorant and traditional Chinese herbal medicine, exhibits antioxidant, anti-inflammatory, and anti-cancer activities. In this study, we aim to investigate the antileukemic effects of SHK and its underlying mechanisms in human CBF-AML cells and zebrafish xenograft models. Our study revealed that SHK reduced the viability of CBF-AML cells. SHK induced cell cycle arrest, promoted cell apoptosis, and induced differentiation in Kasumi-1 cells. Additionally, SHK downregulated the gene expression of AML1-ETO and c-KIT in Kasumi-1 cells. In animal studies, SHK showed no toxic effects in zebrafish and markedly inhibited the growth of leukemia cells in zebrafish xenografts. Transcriptomic analysis showed that differentially expressed genes (DEGs) altered by SHK are linked to key biological processes like DNA repair, replication, cell cycle regulation, apoptosis, and division. Furthermore, KEGG pathways associated with cell growth, such as the cell cycle and p53 signaling pathway, were significantly enriched by DEGs. Analysis of AML-associated genes in response to SHK treatment using DisGeNET and the STRING database indicated that SHK downregulates the expression of cell division regulators regarding AML progression. Finally, we found that SHK combined with cytarabine synergistically reduced the viability of Kasumi-1 cells. In conclusion, our findings provide novel insights into the mechanisms of SHK in suppressing leukemia cell growth, suggesting its potential as a chemotherapeutic agent for human CBF-AML.
核心结合因子急性髓细胞白血病（CBF-AML）是成人 AML 中最常见的类型，其特征是涉及 CBF 基因的特定染色体重排，特别是 t(8;21)。紫草素（SHK）是一种广泛用作食品着色剂和中药的萘醌类植物化学物质，具有抗氧化、抗炎和抗癌作用。在这项研究中，我们旨在研究 SHK 在人 CBF-AML 细胞和斑马鱼异种移植模型中的抗白血病作用及其潜在机制。我们的研究表明，SHK 降低了 CBF-AML 细胞的活力。SHK 诱导细胞周期停滞，促进细胞凋亡，并诱导 Kasumi-1 细胞分化。此外，SHK 下调了 Kasumi-1 细胞中 AML1-ETO 和 c-KIT 的基因表达。在动物研究中，SHK 在斑马鱼中没有毒性作用，并显著抑制了斑马鱼异种移植中白血病细胞的生长。转录组分析表明，SHK 改变的差异表达基因（DEGs）与关键的生物学过程有关，如 DNA 修复、复制、细胞周期调控、凋亡和分裂。此外，与细胞生长相关的 KEGG 途径，如细胞周期和 p53 信号通路，也被 DEGs 显著富集。使用 DisGeNET 和 STRING 数据库分析 SHK 处理后与 AML 相关的基因表明，SHK 下调了与 AML 进展相关的细胞分裂调节剂的表达。最后，我们发现 SHK 与阿糖胞苷联合使用可协同降低 Kasumi-1 细胞的活力。总之，我们的研究结果为 SHK 抑制白血病细胞生长的机制提供了新的见解，表明其作为人类 CBF-AML 化疗药物的潜力。
