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

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Abstract

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.

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Author notes

  1. These authors contributed equally to this work.

Authors and Affiliations

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

    Zhen Lu, Qian Lai, Zhi-feng Li, Meng-ya Zhong, Yue-long Jiang, Li-ying Feng, Jie Zha, Jing-wei Yao & Bing Xu

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

    Zhen Lu, Qian Lai, Zhi-feng Li, Meng-ya Zhong, Yue-long Jiang, Li-ying Feng, Jie Zha, Jing-wei Yao & Bing Xu

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

    Yin Li

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

    Xian-ming Deng

Authors
  1. Zhen Lu
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  2. Qian Lai
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Corresponding authors

Correspondence to Yin Li, Xian-ming Deng or Bing Xu.

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The authors have declared that they have no conflicts of interest.

Additional information

This research was 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), and the Fundamental Research Funds for the Central Universities of China (No. 20720190101).

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Lu, Z., Lai, Q., Li, Zf. et al. Novel PIKfyve/Tubulin Dual-target Inhibitor as a Promising Therapeutic Strategy for B-cell Acute Lymphoblastic Leukemia. CURR MED SCI 44, 298–308 (2024). https://doi.org/10.1007/s11596-024-2847-5

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  • DOI: https://doi.org/10.1007/s11596-024-2847-5

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