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

作　　者：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 

机构地区：[1]Department of Hematology,The First Affiliated Hospital of Xiamen University and Institute of Hematology,School of Medicine,Xiamen University,Xiamen,361005,China [2]Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy,Xiamen,361005,China [3]Department of Oncology,The First Affiliated Hospital of Jinan University,Jinan University,Guangzhou,510630,China [4]State Key Laboratory of Cellular Stress Biology,Innovation Center for Cell Signaling Network,School of Life Sciences,Xiamen University,Xiamen,361003,China

出　　处：《Current Medical Science》2024年第2期298-308,共11页当代医学科学（英文）

基　　金：funded by the National Natural Science Foundation of China(No.81770126,No.81900160,No.81800163,No.22025702,and No.91853203);the Fujian Natural Science Foundation of China(No.2020J011246 and No.2021J011359);the Foundation of Health and Family Planning Commission of Fujian Province of China(No.2020GGB054);the Xiamen Municipal Bureau of Science and Technology(No.3502Z20209003);the Fundamental Research Funds for the Central Universities of China(No.20720190101).

摘　　要：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.

关 键 词：B-cell acute lymphoblastic leukemia dual-target inhibitor NF-KB c-Myc PI3K/AKT p53 

分 类 号：R733.71[医药卫生—肿瘤]