评估新型蛋白磷酸酶2A激活剂作为神经母细胞瘤治疗药物的临床前研究
Pre-Clinical Study Evaluating Novel Protein Phosphatase 2A Activators as Therapeutics for Neuroblastoma.
作者信息
Bownes Laura V, Marayati Raoud, Quinn Colin H, Beierle Andee M, Hutchins Sara C, Julson Janet R, Erwin Michael H, Stewart Jerry E, Mroczek-Musulman Elizabeth, Ohlmeyer Michael, Aye Jamie M, Yoon Karina J, Beierle Elizabeth A
机构信息
Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
Division of Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
出版信息
Cancers (Basel). 2022 Apr 13;14(8):1952. doi: 10.3390/cancers14081952.
BACKGROUND
Protein phosphatase 2A (PP2A) functions as an inhibitor of cancer cell proliferation, and its tumor suppressor function is attenuated in many cancers. Previous studies utilized FTY720, an immunomodulating compound known to activate PP2A, and demonstrated a decrease in the malignant phenotype in neuroblastoma. We wished to investigate the effects of two novel PP2A activators, ATUX-792 (792) and DBK-1154 (1154).
METHODS
Long-term passage neuroblastoma cell lines and human neuroblastoma patient-derived xenograft (PDX) cells were used. Cells were treated with 792 or 1154, and viability, proliferation, and motility were examined. The effect on tumor growth was investigated using a murine flank tumor model.
RESULTS
Treatment with 792 or 1154 resulted in PP2A activation, decreased cell survival, proliferation, and motility in neuroblastoma cells. Immunoblotting revealed a decrease in MYCN protein expression with increasing concentrations of 792 and 1154. Treatment with 792 led to tumor necrosis and decreased tumor growth in vivo.
CONCLUSIONS
PP2A activation with 792 or 1154 decreased survival, proliferation, and motility of neuroblastoma in vitro and tumor growth in vivo. Both compounds resulted in decreased expression of the oncogenic protein MYCN. These findings indicate a potential therapeutic role for these novel PP2A activators in neuroblastoma.
背景
蛋白磷酸酶2A（PP2A）作为癌细胞增殖的抑制剂发挥作用，其肿瘤抑制功能在许多癌症中减弱。先前的研究使用FTY720，一种已知可激活PP2A的免疫调节化合物，并证明神经母细胞瘤的恶性表型有所降低。我们希望研究两种新型PP2A激活剂ATUX-792（792）和DBK-1154（1154）的作用。
方法
使用长期传代的神经母细胞瘤细胞系和源自人类神经母细胞瘤患者的异种移植（PDX）细胞。用792或1154处理细胞，并检测细胞活力、增殖和运动能力。使用小鼠侧腹肿瘤模型研究对肿瘤生长的影响。
结果
用792或1154处理导致PP2A激活，神经母细胞瘤细胞的细胞存活、增殖和运动能力降低。免疫印迹显示，随着792和1154浓度的增加，MYCN蛋白表达降低。用792处理导致体内肿瘤坏死并减少肿瘤生长。
结论
用792或1154激活PP2A可降低神经母细胞瘤在体外的存活、增殖和运动能力以及在体内的肿瘤生长。两种化合物均导致致癌蛋白MYCN的表达降低。这些发现表明这些新型PP2A激活剂在神经母细胞瘤中具有潜在的治疗作用。
Zotero 插件