Abstract 4614: Identification of two salinomycin binding targets in neuroblastoma

Abstract

Abstract Salinomycin, a widely used anti-coccidial agent isolated from a Streptomyces albus strain, was recently identified from a library of 16,000 natural and commercial chemical compounds based on its highly selective inhibitory effect on breast cancer stem cells (CSCs), with more than 100-fold greater potency than paclitaxel. Salinomycin also exhibits cytotoxic effects on other types of cancer cells and CSCs and overcomes drug resistance. However, the exact mechanism of salinomycin, especially its direct binding target(s), and its effects on neuroblastoma (NB) are yet not known. NB is one of the most common solid tumors in children and infants, and a leading cause of mortality in children. Despite advances in diagnosis and treatment, currently, 35% of patients with NB remain incurable. In addition, the majority survivors of NB suffer from long-term side effects of current therapies and are at risk for disease relapse or getting a second, different cancer. More effective therapies are pressingly needed. Since the existence of CSCs in human NB cell lines and NB tumors from patients has been well documented, and has been closely associated with chemoresistance or tumor relapse, therapeutic targeting of NB CSCs may be a critical novel approach to conquer the challenges in NB therapy. Aiming to improve NB therapy, we examined the efficacy and mechanism of salinomycin in human NB cells. Our study showed that salinomycin markedly inhibits NB cell proliferation and tumorsphere formation. Treatment of salinomycin induced G2 cell cycle arrest with an up-regulation of Cyclin A and a down-regulation of p21 protein levels. We further identified TIF1β and NCL as novel direct binding proteins of salinomycin by using comprehensive methods, including chemical proteomics and functional genomics. Furthermore, by analyzing tumor samples from a cohort of 88 NB patients, we found that the elevated level of these proteins is associated with poor prognosis for NB patients. Thus, our results indicate salinomycin is a potential new therapeutic agent and TIF1β and NCL as new therapeutic targets/biomakers for NB therapy. Citation Format: Shuang Zhou, Fengfei Wang, Shi-Hua Xiang, Eric T. Wong, Wallace W. Muhonen, Ekokobe Fonkem, Tze-chen Hsieh, David W. Li, Ruiwen Zhang, John B. Shabb, Joseph M. Wu, Min Wu, Erxi Wu. Identification of two salinomycin binding targets in neuroblastoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4614. doi:10.1158/1538-7445.AM2014-4614