Waters Alicia M, Stewart Jerry E, Atigadda Venkatram R, Mroczek-Musulman Elizabeth, Muccio Donald D, Grubbs Clinton J, Beierle Elizabeth A
University of Alabama, Birmingham, Birmingham, Alabama.
Mol Cancer Ther. 2015 Jul;14(7):1559-69. doi: 10.1158/1535-7163.MCT-14-1103. Epub 2015 May 5.
Neuroblastoma remains a common cause of pediatric cancer deaths, especially for children who present with advanced stage or recurrent disease. Currently, retinoic acid therapy is used as maintenance treatment to induce differentiation and reduce tumor recurrence following induction therapy for neuroblastoma, but unavoidable side effects are seen. A novel retinoid, UAB30, has been shown to generate negligible toxicities. In the current study, we hypothesized that UAB30 would have a significant impact on multiple neuroblastoma cell lines in vitro and in vivo. Cellular survival, cell-cycle analysis, migration, and invasion were studied using AlamarBlue assays, FACS, and Transwell assays, respectively, in multiple cell lines following treatment with UAB30. In addition, an in vivo murine model of human neuroblastoma was utilized to study the effects of UAB30 upon tumor xenograft growth and animal survival. We successfully demonstrated decreased cellular survival, invasion, and migration, cell-cycle arrest, and increased apoptosis after treatment with UAB30. Furthermore, inhibition of tumor growth and increased survival was observed in a murine neuroblastoma xenograft model. The results of these in vitro and in vivo studies suggest a potential therapeutic role for the low toxicity synthetic retinoid X receptor selective agonist, UAB30, in neuroblastoma treatment.
神经母细胞瘤仍然是儿童癌症死亡的常见原因，尤其是对于那些患有晚期或复发性疾病的儿童。目前，维甲酸疗法被用作维持治疗，以诱导神经母细胞瘤诱导治疗后的分化并降低肿瘤复发率，但会出现不可避免的副作用。一种新型类维生素A化合物UAB30已被证明产生的毒性可忽略不计。在本研究中，我们假设UAB30在体外和体内对多种神经母细胞瘤细胞系会有显著影响。在用UAB30处理后的多种细胞系中，分别使用AlamarBlue检测法、流式细胞术和Transwell检测法研究细胞存活、细胞周期分析、迁移和侵袭情况。此外，利用人神经母细胞瘤的体内小鼠模型研究UAB30对肿瘤异种移植生长和动物存活的影响。我们成功证明，用UAB30处理后，细胞存活、侵袭和迁移减少，细胞周期停滞，凋亡增加。此外，在小鼠神经母细胞瘤异种移植模型中观察到肿瘤生长受到抑制且存活期延长。这些体外和体内研究结果表明，低毒性合成视黄酸X受体选择性激动剂UAB30在神经母细胞瘤治疗中具有潜在的治疗作用。
