Nanostructured toxins for the selective destruction of drug-resistant human CXCR4+ colorectal cancer stem cells

Current therapies fail to eradicate colorectal Cancer Stem Cells (CSCs). One of the proposed reasons for this failure is the selection, by chemotherapy exposure, of resistant cells responsible for tumor recurrence. In this regard, CXCR4 overexpression in tumor associates with resistance and poor pro...

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Detalles Bibliográficos
Autores: Serna, Naroa|||0000-0001-5682-8198, Álamo, Patricia|||0000-0003-0510-5701, Ramesh, Prashanthi, Vinokurova, Daria, Sánchez-García, Laura|||0000-0002-8420-1701, Unzueta Elorza, Ugutz|||0000-0001-5119-2266, Gallardo, Alberto|||0000-0002-2514-2027, Céspedes, María Virtudes|||0000-0003-2956-5833, Vázquez, Esther|||0000-0003-1052-0424, Villaverde, Antonio|||0000-0002-2615-4521, Mangues, Ramon|||0000-0003-2661-9525, Medema, Jan Paul
Tipo de recurso: artículo
Fecha de publicación:2020
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:233722
Acceso en línea:https://ddd.uab.cat/record/233722
https://dx.doi.org/urn:doi:10.1016/j.jconrel.2020.01.019
Access Level:acceso abierto
Palabra clave:Protein nanoparticles
Genetic engineering
Self-assembling
Drug delivery
Cancer stem cells
Cell signaling
Descripción
Sumario:Current therapies fail to eradicate colorectal Cancer Stem Cells (CSCs). One of the proposed reasons for this failure is the selection, by chemotherapy exposure, of resistant cells responsible for tumor recurrence. In this regard, CXCR4 overexpression in tumor associates with resistance and poor prognosis in colorectal cancer (CRC) patients. In this study, the effectiveness of engineered CXCR4-targeted self-assembling toxin nanoparticles has been explored in the selective killing of CXCR4 human colon-CSCs compared to 5-Fluorouracil and Oxaliplatin, both classical CRC chemotherapeutic agents. To assess this, 3D spheroid colon-CSCs cultures directly derived from CRC patients and CRC-CSC spheroid-derived tumor mouse models were developed. In these animal models, nanostructured toxins show highly selective induction of pyroptosis in the absence of apoptosis, thus having a great potential to overcome tumor resistance, since the same tumor models show resistance to chemotherapeutics. Results set the basis for further development of more efficient therapies focused on selective CXCR4 CSCs elimination activating non-apoptotic mechanisms and represent a pre-clinical proof of concept for the use of CSCs-targeted nanostructured toxins as protein drugs for CRC therapy.

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