Luo Yiming, Zhao Haijun, Zhu Jingtao, Zhang Liyi, Zha Jie, Zhang Li, Ding Yi, Jian Xinyi, Xia Junjie, Xu Bing, Qi Zhongquan
Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, Fujian, China.
Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen, Fujian, China.
Cancer Med. 2023 Sep;12(18):18901-18917. doi: 10.1002/cam4.6480. Epub 2023 Sep 1.
Acute myeloid leukemia (AML) is a highly aggressive form of cancer that is frequently diagnosed in adults and small molecule inhibitors have gained significant attention as a potential treatment option for AML.
The up-regulated genes in AML were identified through bioinformatics analysis. Potential candidate agents were selected through pharmacogenomics analysis. Proteomic experiments were conducted to determine the molecular mechanism after inhibitor treatment. To evaluate drug synergy, both cellular functional experiments and an AML mouse model were used.
Through bioinformatics analysis, we conducted a screening for genes that are highly expressed in AML, which led to the identification of nine small-molecule inhibitors. Among these inhibitors, the PI3K/mTOR inhibitor VS-5584 demonstrated significant effectiveness in inhibiting AML cell proliferation at low concentrations. Further testing revealed that VS-5584 induced apoptosis and cycle arrest of AML cells in a dose- and time-dependent manner. Proteomics analysis showed significant changes in protein expression profiles of AML cells after VS-5584 treatment, with 287 proteins being down-regulated and 71 proteins being up-regulated. The proteins that exhibited differential expression were primarily involved in regulating the cell cycle and apoptosis, as determined by GO analysis. Additionally, KEGG analysis indicated that the administration of VS-5584 predominantly affected the P53 and SIRT2 signaling pathways. The use of SIRT2 inhibitor SirReal2 alongside VS-5584 caused a significant reduction in the half-maximal inhibitory concentration (IC ) of VS-5584 on AML cells. In vivo, experiments suggested that VS-5584 combined with SirReal2 suppressed tumor growth in the subcutaneous model and extended the survival rate of mice injected with tumor cells via tail vein.
Taken together, the PI3K/mTOR inhibitor VS-5584 was effective in suppressing AML cell proliferation. PI3K/mTOR inhibitor combined with SIRT2 inhibitor exhibited a synergistic inhibitory effect on AML cells. Our findings offer promising therapeutic strategies and drug candidates for the treatment of AML.
急性髓系白血病（AML）是一种侵袭性很强的癌症，常见于成年人，小分子抑制剂作为AML的一种潜在治疗选择已受到广泛关注。
通过生物信息学分析确定AML中上调的基因。通过药物基因组学分析选择潜在的候选药物。进行蛋白质组学实验以确定抑制剂处理后的分子机制。为评估药物协同作用，使用了细胞功能实验和AML小鼠模型。
通过生物信息学分析，我们对AML中高表达的基因进行了筛选，从而鉴定出9种小分子抑制剂。在这些抑制剂中，PI3K/mTOR抑制剂VS-5584在低浓度下对抑制AML细胞增殖显示出显著效果。进一步测试表明，VS-5584以剂量和时间依赖性方式诱导AML细胞凋亡和细胞周期停滞。蛋白质组学分析显示，VS-5584处理后AML细胞的蛋白质表达谱发生了显著变化，287种蛋白质下调，71种蛋白质上调。通过基因本体（GO）分析确定，差异表达的蛋白质主要参与调节细胞周期和凋亡。此外，京都基因与基因组百科全书（KEGG）分析表明，给予VS-5584主要影响P53和SIRT2信号通路。将SIRT2抑制剂SirReal2与VS-5584联合使用可显著降低VS-5584对AML细胞的半数最大抑制浓度（IC）。在体内，实验表明VS-5584与SirReal2联合使用可抑制皮下模型中的肿瘤生长，并延长经尾静脉注射肿瘤细胞的小鼠的存活率。
综上所述，PI3K/mTOR抑制剂VS-5584可有效抑制AML细胞增殖。PI3K/mTOR抑制剂与SIRT2抑制剂联合使用对AML细胞具有协同抑制作用。我们的研究结果为AML的治疗提供了有前景的治疗策略和候选药物。
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