Preclinical Evaluation of a Novel RXR Agonist for the Treatment of Neuroblastoma

• Published in: Molecular cancer therapeutics 2015-07, Vol.14 (7), p.1559-1569
• Main Authors: Waters, Alicia M, Stewart, Jerry E, Atigadda, Venkatram R, Mroczek-Musulman, Elizabeth, Muccio, Donald D, Grubbs, Clinton J, Beierle, Elizabeth A
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Caspase 3 - metabolism; Cell Cycle Checkpoints - drug effects; Cell Differentiation - drug effects; Cell Line, Tumor; Cell Movement - drug effects; Cell Survival - drug effects; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Fatty Acids, Unsaturated - therapeutic use; Female; Flow Cytometry; Humans; Immunoblotting; Mice, Nude; Naphthalenes - therapeutic use; Neuroblastoma - drug therapy; Neuroblastoma - pathology; Retinoid X Receptors - agonists; Survival Analysis; Tumor Burden - drug effects; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-14-1103

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.