首页|Novel PIKfyve/Tubulin Dual-target Inhibitor as a Promising Therapeutic Strategy for B-cell Acute Lymphoblastic Leukemia

Novel PIKfyve/Tubulin Dual-target Inhibitor as a Promising Therapeutic Strategy for B-cell Acute Lymphoblastic Leukemia

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Objective:In B-cell acute lymphoblastic leukemia(B-ALL),current intensive chemotherapies for adult patients fail to achieve durable responses in more than 50％of cases,underscoring the urgent need for new therapeutic regimens for this patient population.The present study aimed to determine whether HZX-02-059,a novel dual-target inhibitor targeting both phosphatidylinositol-3-phosphate 5-kinase(PIKfyve)and tubulin,is lethal to B-ALL cells and is a potential therapeutic for B-ALL patients.Methods:Cell proliferation,vacuolization,apoptosis,cell cycle,and in-vivo tumor growth were evaluated.In addition,Genome-wide RNA-sequencing studies were conducted to elucidate the mechanisms of action underlying the anti-leukemia activity of HZX-02-059 in B-ALL.Results:HZX-02-059 was found to inhibit cell proliferation,induce vacuolization,promote apoptosis,block the cell cycle,and reduce in-vivo tumor growth.Downregulation of the p53 pathway and suppression of the phosphoinositide 3-kinase(PI3K)/AKT pathway and the downstream transcription factors c-Myc and NF-κB were responsible for these observations.Conclusion:Overall,these findings suggest that HZX-02-059 is a promising agent for the treatment of B-ALL patients resistant to conventional therapies.

B-cell acute lymphoblastic leukemiadual-target inhibitorNF-κBc-MycPI3K/AKTp53

Zhen LU、Qian LAI、Zhi-feng LI、Meng-ya ZHONG、Yue-long JIANG、Li-ying FENG、Jie ZHA、Jing-wei YAO、Yin LI、Xian-ming DENG、Bing XU

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Department of Hematology,The First Affiliated Hospital of Xiamen University and Institute of Hematology,School of Medicine,Xiamen University,Xiamen 361005,China

Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy,Xiamen 361005,China

Department of Oncology,The First Affiliated Hospital of Jinan University,Jinan University,Guangzhou 510630,China

State Key Laboratory of Cellular Stress Biology,Innovation Center for Cell Signaling Network School of Life Sciences,Xiamen University,Xiamen 361003,China

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National Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaFujian Natural Science Foundation of ChinaFujian Natural Science Foundation of ChinaFoundation of Health and Family Planning Commission of Fujian Province of ChinaXiamen Municipal Bureau of Science and TechnologyFundamental Research Funds for the Central Universities of China

81770126819001608180016322025702918532032020J0112462021J0113592020GGB0543 502Z2020900320720190101

2024

10.1007/s11596-024-2847-5

当代医学科学(英文)
华中科技大学同济医学院

当代医学科学(英文)

影响因子：0.748
ISSN：2096-5230
年,卷(期)：2024.44(2)
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