Virtual screening-driven repositioning of etoposide as CD44 antagonist in breast cancer cells
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Charmina Aguirre-Alvarado1, Aldo Segura-Cabrera2, Inés Velázquez-Quesada3, Miguel A. Hernández-Esquivel3, Carlos A. García-Pérez4, Sandra L. Guerrero-Rodríguez1, Angel J. Ruiz-Moreno1, Andrea Rodríguez-Moreno1, Sonia M. Pérez-Tapia3, Marco A. Velasco-Velázquez1
1Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), México D.F., México
2Red de Estudios Moleculares Avanzados, Instituto de Ecología (INECOL) A.C., Clúster Científico y Tecnológico Biomimic®, Xalapa Veracruz, México
3Unidad de Desarrollo e Investigación en Bioprocesos, Escuela Nacional de Ciencias Biológicas-IPN, México D.F., México
4Centro de Biotecnología Genómica-IPN, Reynosa, Tamaulipas, México
Marco A. Velasco-Velázquez, e-mail: firstname.lastname@example.org
Keywords: etoposide, CD44, breast cancer, epithelial-mesenchymal transition, cancer stem cells
Received: December 22, 2015 Accepted: March 02, 2016 Published: March 18, 2016
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.
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