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

Mol Cancer. 2019 Nov 13;18(1):159. doi: 10.1186/s12943-019-1068-1.

Abstract

Background: Uveal 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.

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.

Results: 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.

Conclusions: Our 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.

Keywords: Cancer stem-like cells; Metastasis; Salinomycin; Twist1; Uveal melanoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Humans
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / secondary*
  • Melanoma / metabolism*
  • Melanoma / pathology*
  • Membrane Potential, Mitochondrial
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Molecular Structure
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism*
  • Pyrans / chemistry
  • Pyrans / pharmacology*
  • Uveal Neoplasms / metabolism*
  • Uveal Neoplasms / pathology*
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Pyrans
  • salinomycin

Supplementary concepts

  • Uveal melanoma