Evaluation of the Activity of Monensin and Its Analogs for Modulation of Stem-like Cell Functionality in 2D and 3D Breast Cancer Models

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Abstract
Monensin (MON) is a polyether ionophore antibiotic of natural origin and is an FDA-approved drug for veterinary use. Recent studies have highlighted its potential anticancer activity in various in vitro and in vivo models. In this study, we evaluated the anti-breast cancer activity of MON and 37 synthetic analog compounds using cell monolayer and organoid models. Through a mini-ring cell viability assay, several compounds were identified that were more potent and selective against breast cancer cells compared to non-cancerous cells, surpassing the activity of parent MON. MON and these compounds induced significant DNA fragmentation, reduced cell migration, and downregulated SOX2 expression. Furthermore, MON and the most potent analog, compound 12, reduced the percentage of CD44+/CD24-/low stem-like cells and diminished colony formation properties. Proteomics analyses revealed that several pathways, including extracellular matrix organization, were significantly dysregulated by MON and compound 12 in breast cancer cells. Among these, TIMP2, a protein associated with the suppression of tumor growth and metastasis, was identified as one of the most prominently upregulated proteins by MON and compound 12 in MDA-MB-231 cells. This finding was also validated in other breast cancer and melanoma cell lines. To simulate breast cancer metastasis to the brain, a human hybrid organoid system: tumor in brain organoid (HOSTBO) model was developed. MON and compound 12 significantly reduced Ki-67 expression within the HOSTBOs, and compound 12 significantly downregulated SOX2 expression. Collectively, MON and compound 12 significantly reduced the proliferation of breast cancer stem-like cells in the organoid models, inhibited their migration, and dysregulated markers associated with stemness, demonstrating their potential as anti-metastatic agents and warranting further clinical development.
Funding Information
  • National Center for Advancing Translational Sciences (K12 TR004924, KL2 TR003108, UL1 TR003107, UM1 TR004909)
  • National Institute of Diabetes and Digestive and Kidney Diseases (RO1 DK139476)
  • University of Arkansas for Medical Sciences
  • National Institute of General Medical Sciences (R24 GM137786)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01 HD093461)
  • Barton Pilot

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