目的:在B细胞急性淋巴细胞白血病(B-ALL)中,目前,成人患者的强化化疗在超过50%的病例中未能达到持久的反应,强调该患者人群迫切需要新的治疗方案。本研究旨在确定HZX-02-059,一种靶向磷脂酰肌醇-3-磷酸5-激酶(PIKfyve)和微管蛋白的新型双靶点抑制剂,对B-ALL细胞是致命的,是B-ALL患者的潜在治疗方法。
方法:细胞增殖,真空化,凋亡,细胞周期,和体内肿瘤生长进行了评估。此外,进行全基因组RNA测序研究以阐明HZX-02-059在B-ALL中抗白血病活性的作用机制。
结果:发现HZX-02-059抑制细胞增殖,诱导空泡化,促进细胞凋亡,阻断细胞周期,减少体内肿瘤生长。p53途径的下调和磷酸肌醇3-激酶(PI3K)/AKT途径和下游转录因子c-Myc和NF-κB的抑制是这些观察结果的原因。
结论:总体而言,这些研究结果表明,HZX-02-059是治疗对常规疗法耐药的B-ALL患者的有前景的药物.
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.
CONCLUSIONS: Overall, these findings suggest that HZX-02-059 is a promising agent for the treatment of B-ALL patients resistant to conventional therapies.