Salinomycin effectively eliminates cancer stem-like cells and obviates hepatic metastasis in uveal melanoma

Abstract

BackgroundUveal melanoma (UM) is the most common primary intraocular tumor. Hepatic metastasis is the major and direct death-related reason in UM patients. 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 against CSCs thereby restrain hepatic metastasis in UM. The objective of the study is to explore the antitumor activity of salinomycin against UM and clarify its underlying mechanism.MethodsUM 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.ResultsWe 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.ConclusionsOur findings suggest that targeting UM CSCs by salinomycin is a promising therapeutic strategy to hamper hepatic metastasis in UM. These results provide the first pre-clinical evidence for further testing of salinomycin for its antitumor efficacy in UM patients with hepatic metastasis.

The Essential Factors of Establishing Patient-derived Tumor Model

“…Dong et al used NOD/SCID to establish non-small cell lung cancer PDX model with 90% engraftment rate, and examined for determining responses to conventional chemotherapeutic regimens 46 . Zhou and colleagues evaluated antitumor activity of salinomycin in the NOD/SCID Uveal melanoma xenograft model, and certificated NOD/SCID is effective host for melanoma preclinical research 52 . Likewise, Kimple et al established head and neck cancer PDX with 85% engraftment rate via NSG.…”

Evaluation of the Influence of Adalimumab on the Expression Profile of Leptin-Related Genes and Proteins in Keratinocytes Treated with Lipopolysaccharide A

“…The activation of caspase-8/-10 activates a cascade of caspases connected with the proteolysis of enzymes and structural proteins of cells and is characteristic of the extrinsic pathway of apoptosis (independent of mitochondria), beginning the proteolysis of enzymes and cellular structure proteins which occurs in cascades. On the other hand, the key role in the intrinsic pathway (otherwise known as the mitochondrial pathway) is played by caspases-3, -6, -7 [ 35 ]. Therefore, it seems that adalimumab induces apoptosis through the pathway dependent on mitochondria [ 36 ].…”

<p>Research Progress of Cancer Stem Cells in Uveal Melanoma</p>

“…The effect of drugs and its action pathway on UM-CSC were investigated by Pan and colleagues in China in which they used aldehyde dehydrogenase assay, transwell migration and invasion assay, melanosphere culture and xenograft experiment to identify the existence of CSC. 11,12 In addition, tumor…”

“…The effect of drugs and its action pathway on UM-CSC were investigated by Pan and colleagues in China in which they used aldehyde dehydrogenase assay, transwell migration and invasion assay, melanosphere culture and xenograft experiment to identify the existence of CSC. 11 , 12 In addition, tumor transendothelial migration assay, anoikis resistance assessment and other possible markers of UM-CSC (such as CD166, Nestin, etc.) were also used to identify CSC and its characteristics.…”