TY - JOUR
T1 - Nanostructured toxins for the selective destruction of drug-resistant human CXCR4+ colorectal cancer stem cells
AU - Serna, Naroa
AU - Álamo, Patricia
AU - Ramesh, Prashanthi
AU - Vinokurova, Daria
AU - Sánchez-García, Laura
AU - Unzueta, Ugutz
AU - Gallardo, Alberto
AU - Céspedes, María Virtudes
AU - Vázquez, Esther
AU - Villaverde, Antonio
AU - Mangues, Ramón
AU - Medema, Jan Paul
PY - 2020/4/10
Y1 - 2020/4/10
N2 - 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.
AB - 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.
KW - Cancer stem cells
KW - Cell signaling
KW - Drug delivery
KW - Genetic engineering
KW - Protein nanoparticles
KW - Self-assembling
UR - http://www.scopus.com/inward/record.url?scp=85078511457&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.jconrel.2020.01.019
DO - https://doi.org/10.1016/j.jconrel.2020.01.019
M3 - Article
C2 - 31931052
SN - 0168-3659
VL - 320
SP - 96
EP - 104
JO - Journal of controlled release
JF - Journal of controlled release
ER -