Virtual screening-driven repositioning of etoposide as CD44 antagonist in breast cancer cells
| Autor: | Inés Velázquez-Quesada, Aldo Segura-Cabrera, Sandra L. Guerrero-Rodríguez, Charmina Aguirre-Alvarado, Carlos A. García-Pérez, Sonia Mayra Pérez-Tapia, Andrea Rodríguez-Moreno, Angel J Ruiz-Moreno, Miguel A. Hernandez-Esquivel, Marco A. Velasco-Velázquez |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
cancer stem cells
0301 basic medicine Epithelial-Mesenchymal Transition Apoptosis Breast Neoplasms Molecular Dynamics Simulation etoposide 03 medical and health sciences breast cancer 0302 clinical medicine Cancer stem cell Biomarkers Tumor Tumor Cells Cultured medicine Humans Epithelial–mesenchymal transition Hyaluronic Acid CD44 Cell adhesion Etoposide Cell Proliferation Gene knockdown biology Cell growth Chemistry Drug Repositioning CD24 Antigen Cell migration Antineoplastic Agents Phytogenic High-Throughput Screening Assays Molecular Docking Simulation Hyaluronan Receptors 030104 developmental biology Oncology 030220 oncology & carcinogenesis Immunology Cancer research biology.protein Female Signal Transduction Research Paper medicine.drug |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.8180 |
| Popis: | CD44 is a receptor for hyaluronan (HA) that promotes epithelial-to-mesenchymal transition (EMT), induces cancer stem cell (CSC) expansion, and favors metastasis. Thus, CD44 is a target for the development of antineoplastic agents. In order to repurpose drugs as CD44 antagonists, we performed consensus-docking studies using the HA-binding domain of CD44 and 11,421 molecules. Drugs that performed best in docking were examined in molecular dynamics simulations, identifying etoposide as a potential CD44 antagonist. Ligand competition and cell adhesion assays in MDA-MB-231 cells demonstrated that etoposide decreased cell binding to HA as effectively as a blocking antibody. Etoposide-treated MDA-MB-231 cells developed an epithelial morphology; increased their expression of E-cadherin; and reduced their levels of EMT-associated genes and cell migration. By gene expression analysis, etoposide reverted an EMT signature similarly to CD44 knockdown, whereas other topoisomerase II (TOP2) inhibitors did not. Moreover, etoposide decreased the proportion of CD44+/CD24− cells, lowered chemoresistance, and blocked mammosphere formation. Our data indicate that etoposide blocks CD44 activation, impairing key cellular functions that drive malignancy, thus rendering it a candidate for further translational studies and a potential lead compound in the development of new CD44 antagonists. |
| Databáze: | OpenAIRE |
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