title: Virtual screening-driven repositioning of etoposide as CD44 antagonist in breast cancer cells.
abstract: 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.
authors.affiliation: Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), México D.F., México.
authors.forename: Charmina
authors.initials: C
authors.lastname: Aguirre-Alvarado
authors.affiliation: Red de Estudios Moleculares Avanzados, Instituto de Ecología (INECOL) A.C., Clúster Científico y Tecnológico Biomimic®, Xalapa, Veracruz, México.
authors.forename: Aldo
authors.initials: A
authors.lastname: Segura-Cabrera
authors.affiliation: Unidad de Desarrollo e Investigación en Bioprocesos, Escuela Nacional de Ciencias Biológicas-IPN, México D.F., México.
authors.forename: Inés
authors.initials: I
authors.lastname: Velázquez-Quesada
authors.affiliation: Unidad de Desarrollo e Investigación en Bioprocesos, Escuela Nacional de Ciencias Biológicas-IPN, México D.F., México.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Hernández-Esquivel
authors.affiliation: Centro de Biotecnología Genómica-IPN, Reynosa, Tamaulipas, México.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: García-Pérez
authors.affiliation: Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), México D.F., México.
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Guerrero-Rodríguez
authors.affiliation: Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), México D.F., México.
authors.forename: Angel J
authors.initials: AJ
authors.lastname: Ruiz-Moreno
authors.affiliation: Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), México D.F., México.
authors.forename: Andrea
authors.initials: A
authors.lastname: Rodríguez-Moreno
authors.affiliation: Unidad de Desarrollo e Investigación en Bioprocesos, Escuela Nacional de Ciencias Biológicas-IPN, México D.F., México.
authors.forename: Sonia M
authors.initials: SM
authors.lastname: Pérez-Tapia
authors.affiliation: Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), México D.F., México.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Velasco-Velázquez
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051927:CD24 Antigen / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D058492:Drug Repositioning; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005047:Etoposide / Q000494:pharmacology*; D005260:Female; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D018960:Hyaluronan Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006820:Hyaluronic Acid / Q000378:metabolism; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D014408:Biomarkers, Tumor; D051927:CD24 Antigen; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D005047:Etoposide; D006820:Hyaluronic Acid
keywords: CD44; breast cancer; cancer stem cells; epithelial-mesenchymal transition; etoposide