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

  • Curr Med Sci. 2024 Apr;44(2):298-308. doi: 10.1007/s11596-024-2847-5.
Zhen Lu  #  1  2 ,  Qian Lai  #  1  2 ,  Zhi-Feng Li  #  1  2 ,  Meng-Ya Zhong  1  2 ,  Yue-Long Jiang  1  2 ,  Li-Ying Feng  1  2 ,  Jie Zha  1  2 ,  Jing-Wei Yao  1  2 ,  Yin Li  3 ,  Xian-Ming Deng  4 ,  Bing Xu  5  6
Affiliations
  • 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. [email protected].
  • 4. State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, 361003, China. [email protected].
  • 5. Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361005, China. [email protected].
  • 6. Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen, 361005, China. [email protected].
  • # Contributed equally.
PMID: 38619682 DOI: 10.1007/s11596-024-2847-5
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.

Keywords
B-cell acute lymphoblastic leukemia; NF-κB; PI3K/AKT; c-Myc; dual-target inhibitor; p53.
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