TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2020
·
IF 3.347
Xiaolei Wang,Kaiyan Lou,Xiaodong Song,Huijuan Ma,Xinyi Zhou,Huan Xu,Wei Wang
Mebendazole (MBZ) is a tubulin-suppressive antihelmintic agent with low toxicity, which has been repurposed to treat different types of tumors. Chemoresistance is quite common in refractory or relapsed T cell acute lymphoblastic leukemia (T-ALL), which leads to dismal chances of recovery. In this study, MBZ was found to suppress the proliferation and reduce the viability of T-ALL cell line, CCRF-CEM, and its chemoresistant derivative, CEM/C1, at nanomolar concentrations. The inhibitive effects were found to be dose-dependent and not to be affected by the chemoresistance of CEM/C1 cells. Cell cycle arrest, caspase 3/7 activation and tubulin disruption were found in the MBZ-treated T-ALL cells. Notch1 signaling, which is often aberrantly activated in T-ALL cells, was showed to be suppressed by MBZ treatments. MBZ administration in murine T-ALL models also suppressed the growth of CEM/C1 cells, indicating that MBZ may be developed as a therapeutic agent for chemoresistant T-ALLs. The mRNA levels of the Notch1 and Hes1 were also confirmed to be suppressed by MBZ in vivo, which was consistent with the in vitro observations. This study demonstrated, for the first time, that MBZ could inhibit chemoresistant T-ALL cells both in vitro and in vivo , and the Notch1 signaling pathway was suppressed by MBZ treatment.
研究领域:
肿瘤学
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药理学
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细胞生物学
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DOI
PubMed
高影响因子
Biochemistry and Cell Biology
·
2023
·Vol. 102
·期 1
·
IF 2.9
Bin Zhang,Ruowen Sun,Min Gu,Zehui Jiang,Ye Wang,Linlin Zhang,Xiaoyang Liu,Zuofei Chi
Acute T-lymphocyte leukemia (T-ALL) is a malignant tumor disease. RNA-binding protein neotumor ventral antigen-1 (NOVA1) is highly expressed in bone marrow mononuclear cells of T-ALL patients, while the role of NOVA1 in T-ALL progression remains unknown. The gain- and loss-of-function studies for NOVA1 were performed in Jurkat and CCRF-CEM cells. NOVA1 overexpression promoted cell proliferation and cell cycle progression. NOVA1 knockdown increased the apoptosis rate of T-ALL cells. Ubiquitin-specific protease 44 (USP44), a nuclear protein with deubiquitinase catalytic activity, has been reported to play an oncogene role in human T-cell leukemia. USP44 expression was positively associated with NOVA1, and RNA immunoprecipitation assay verified the binding of NOVA1 to the mRNA of USP44. USP44 knockdown partially abolished NOVA1-induced cell proliferation and inhibition of apoptosis. The in vivo xenograft experiment was performed by injection of T-ALL tumor cells into the tail vein of NOD/SCID mice. The knockdown of NOVA1 had lower tumorigenicity. NOVA1 knockdown alleviated pathological changes in lung and spleen tissues, and increased the overall survival period and the weight of T-ALL mice. Thus, NOVA1 acts as an accelerator in T-ALL, and its function might be achieved by binding to and stabilizing USP44 mRNA.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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癌症研究
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DOI
PubMed
高影响因子
Cell Reports Medicine
·
2025
·
IF 10.6
Yong Liu,Zefan Du,Lindi Li,Junbin Huang,Su Liu,Bo Lu,Yifei Duan,Yucai Cheng,Tianwen Li,Jing Zhang,Jiani Mo,Yalin Yang,Wengqing Wang,Hailin Zou,Tianqi Liang,Meng Jiang,Mo Yang,Yun Chen,Cheng Ouyang,Chun Chen
T cell acute lymphoblastic leukemia (T-ALL) is a heterogeneous disease characterized by a high relapse rate. By single-cell transcriptome analysis, we characterize the bone marrow immune microenvironment in patients with T-ALL, identifying 13 major cell clusters. These patients exhibited abnormally expanded hematopoietic stem cells (HSCs) and granulocyte-monocyte progenitors (GMPs), immunosuppressive traits in CD4 + T, CD8 + T, and natural killer (NK) cells. Subdividing CD4 + T cells reveal two subsets transitioning between T helper (Th)1/Th2, Annexin-A1 (ANXA1) − GATA3 − CD4 + T, and ANXA1 + GATA3 + CD4 + T. Additionally, NK cells demonstrate exhaustion in the tumor microenvironment of patients with relapsed T-ALL, with JUN identified as a critical factor. Additionally, JUN is also highly expressed in T-ALL and is crucial for maintaining its proliferation. The JUN inhibitor exhibited successful lethality toward leukemia cells and ameliorated NK cell exhaustion in relapsed T-ALL cell line, as well as in cell-derived tumor xenograft (CDX), patient-derived tumor xenograft (PDX), and NOTCH1-mutant mouse models. In summary, our findings enhance the understanding of T-ALL relapse mechanisms and support the development of innovative immunotherapies for patients with relapsed T-ALL.
研究领域:
血液学
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肿瘤学
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免疫学
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产品关联
DOI
PubMed
高影响因子
Cancers
·
2026
·Vol. 18
·期 19
·3150
·
IF 4.8
Xian Zhang,Zhuping Chen,Yujiao Liu,Dongdong Zhang
Objective:T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive hematological malignancy with poor overall prognosis. This study systematically evaluates the anti-leukemic therapeutic potential and underlying redox-driven mechanisms of PZ2, a novel organic arsenic compound, in T-ALL.Methods:The cytotoxicity of PZ2 against T-ALL cell lines and normal cells was assessed to determine its therapeutic window. RNA-seq was utilized to map transcriptomic alterations. Intracellular redox homeostasis, mitochondrial membrane potential (MMP), cell cycle, and apoptosis were evaluated using flow cytometry and fluorescence microscopy. Ultrastructural changes and key protein expressions were analyzed via TEM, RT-qPCR, and immunoblotting. In vivo efficacy was validated using a T-ALL cell-line-derived xenograft (CDX) mouse model.Results:PZ2 exhibited superior cytotoxicity and an improved safety profile compared to inorganic arsenic trioxide (ATO). Transcriptomic data indicated strong enrichment in apoptosis and autophagy–lysosome pathways. PZ2 induced profound mitochondrial oxidative stress, leading to ROS accumulation, MMP loss, and subsequent activation of caspase-dependent apoptosis—effects that were completely rescued by ROS scavengers. Furthermore, PZ2 triggered G2/M phase arrest and activated autophagic flux (upregulatedGABARAPL1and LC3-II, degraded p62). Notably, pharmacological inhibition of autophagy rescued PZ2-induced apoptosis, revealing a pro-death autophagic mechanism. In vivo, PZ2 significantly suppressed tumor growth and prolonged survival without overt systemic toxicity.Conclusions:PZ2 exhibits potent anti-T-ALL activity that may involve a dual mechanism: ROS-dependent mitochondrial apoptosis and pro-death autophagy potentially associated withGABARAPL1. This novel organic arsenical may represent a promising and potentially safer alternative for leukemia therapy, and these findings suggest a potential interplay between oxidative stress and autophagic cell death.
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DOI
高影响因子
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