Salinomycin Effectively Eliminates Cancer Stem-Like Cells and Obviates Hepatic Metastasis in Uveal Melanoma

Abstract

Background: Uveal melanoma (UM) is the most common primary intraocular tumor. Approximately 50% patients with UM manifest single-organ metastasis to liver, which is the major and drect death reason in the UM patients owing to lack effective chemotherapeutic drugs. Consequently, there is a desperate need for new effective treatment modalities. Given that cancer stem-like cells (CSCs) are roots of metastasis, targeting CSCs may be a promising strategy to overcome hepatic metastasis in UM. Salinomycin, which has been identified as a selective inhibitor of CSCs in multiple types of cancer, may be an attractive agent to against CSCs thereby restrain hepatic metastasis in UM. The objective of the study is to explore the antitumor activity of salinomycin on UM and clarify its underlying mechanism. Methods: UM cells were treated with salinomycin, and its effects on cell proliferation, apoptosis, migration, invasion, CSCs population, and the related signal transduction pathways were determined. The in vivo antitumor activity of salinomycin was evaluated in the NOD/SCID UM xenograft model and intrasplenic transplantation liver metastasis mouse model. Findings: We found that salinomycin remarkably obviated growth and survival in UM cell lines and in a UM xenograft mouse model. Meanwhile, salinomycin significantly eliminated CSCs and efficiently hampered hepatic metastasis in UM liver metastasis mouse model. Mechanistically, Twist1 was fundamental for the salinomycin-enabled CSCs elimination and migration/invasion blockage in UM cells. Interpretation: These findings suggest that salinomycin may be a promising therapeutic agent for UM patients with hepatic metastasis. Funding Statement: This study was supported by grants from the Research Foundation of Education Bureau of Guangdong Province, China (Grant cxzd1103 to J. Pan), and Natural Science Foundation of Guangdong province (Grant 2015A030312014 to J. Pan). Present address of W.D., Y.W., and S.W.: Institute of Tumor Pharmacology, College of Pharmacy, Jinan University, Guangzhou, China. Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: The animal studies were approved by the Sun Yat-sen University Institutional Animal Care and Use Committee.