Division of Pediatric Surgery, Department of Surgery, University of Alabama, Birmingham, Birmingham, AL, United States of America.
Division of Pediatric Hematology Oncology, Department of Pediatrics, University of Alabama, Birmingham, Birmingham, AL, United States of America.
PLoS One. 2019 Apr 10;14(4):e0214469. doi: 10.1371/journal.pone.0214469. eCollection 2019.
Despite an increase in incidence, treatments for hepatoblastoma remain virtually unchanged for the past 20 years, emphasizing the need for novel therapeutics. FTY720 (fingolimod) is an immunomodulator approved for use in multiple sclerosis in children that has been demonstrated to have anti-cancer properties in multiple cancer types. We have demonstrated that FTY720 activates PP2A in hepatoblastoma, but does not do so via inhibition of the endogenous inhibitors, CIP2A and I2PP2A, as previously observed in other cancers. PP2A activation in hepatoblastoma decreased cell viability, proliferation, and motility and induced apoptosis. In a subcutaneous xenograft model, FTY720 decreased tumor growth. FTY720 in combination with the standard chemotherapeutic, cisplatin, decreased proliferation in a synergistic manner. Finally, animals bearing subcutaneous hepatoblastoma xenografts treated with FTY720 and cisplatin in combination had significantly decreased tumor growth compared to those treated with either drug alone. These findings show that targeting PP2A with FTY70 shows promise in the treatment of hepatoblastoma and that combining FTY720 with cisplatin may be a novel and effective strategy to better treat this devastating pediatric liver tumor.
尽管肝癌的发病率有所增加，但在过去的 20 年中，其治疗方法几乎没有改变，这强调了需要新的治疗方法。FTY720（芬戈莫德）是一种已批准用于儿童多发性硬化症的免疫调节剂，已证明其在多种癌症类型中具有抗癌特性。我们已经证明，FTY720 在肝癌中激活了 PP2A，但与先前在其他癌症中观察到的情况不同，它不是通过抑制内源性抑制剂 CIP2A 和 I2PP2A 来实现的。肝癌中 PP2A 的激活降低了细胞活力、增殖和迁移，并诱导了细胞凋亡。在皮下异种移植模型中，FTY720 降低了肿瘤生长。FTY720 与标准化疗药物顺铂联合使用以协同方式降低增殖。最后，与单独使用任一药物相比，接受 FTY720 和顺铂联合治疗的皮下肝癌异种移植动物的肿瘤生长明显减少。这些发现表明，用 FTY70 靶向 PP2A 在治疗肝癌方面具有前景，并且将 FTY720 与顺铂联合使用可能是一种新颖有效的策略，可以更好地治疗这种毁灭性的小儿肝肿瘤。
