학술논문
Potent Anticancer Activity of CXCR4-Targeted Nanostructured Toxins in Aggressive Endometrial Cancer Models.
Document Type
Academic Journal
Author
Medina-Gutiérrez E; Oncogenesis and Antitumor Drugs Group, Institut d'Investigació Biomèdica Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain.; Oncogenesis and Antitumor Drugs Group, Institut de Recerca Contra la Leucèmia Josep Carreras, 08025 Barcelona, Spain.; García-León A; Oncogenesis and Antitumor Drugs Group, Institut d'Investigació Biomèdica Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain.; Oncogenesis and Antitumor Drugs Group, Institut de Recerca Contra la Leucèmia Josep Carreras, 08025 Barcelona, Spain.; Gallardo A; Oncogenesis and Antitumor Drugs Group, Institut d'Investigació Biomèdica Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain.; Department of Pathology, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain.; Álamo P; Oncogenesis and Antitumor Drugs Group, Institut d'Investigació Biomèdica Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain.; Oncogenesis and Antitumor Drugs Group, Institut de Recerca Contra la Leucèmia Josep Carreras, 08025 Barcelona, Spain.; CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), 28029 Madrid, Spain.; Alba-Castellón L; Oncogenesis and Antitumor Drugs Group, Institut d'Investigació Biomèdica Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain.; Oncogenesis and Antitumor Drugs Group, Institut de Recerca Contra la Leucèmia Josep Carreras, 08025 Barcelona, Spain.; Unzueta U; Oncogenesis and Antitumor Drugs Group, Institut d'Investigació Biomèdica Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain.; Oncogenesis and Antitumor Drugs Group, Institut de Recerca Contra la Leucèmia Josep Carreras, 08025 Barcelona, Spain.; CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), 28029 Madrid, Spain.; Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.; Villaverde A; CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), 28029 Madrid, Spain.; Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.; Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.; Vázquez E; CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), 28029 Madrid, Spain.; Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.; Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.; Casanova I; Oncogenesis and Antitumor Drugs Group, Institut d'Investigació Biomèdica Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain.; Oncogenesis and Antitumor Drugs Group, Institut de Recerca Contra la Leucèmia Josep Carreras, 08025 Barcelona, Spain.; CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), 28029 Madrid, Spain.; Mangues R; Oncogenesis and Antitumor Drugs Group, Institut d'Investigació Biomèdica Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain.; Oncogenesis and Antitumor Drugs Group, Institut de Recerca Contra la Leucèmia Josep Carreras, 08025 Barcelona, Spain.; CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), 28029 Madrid, Spain.
Source
Publisher: MDPI Country of Publication: Switzerland NLM ID: 101526829 Publication Model: Electronic Cited Medium: Print ISSN: 2072-6694 (Print) Linking ISSN: 20726694 NLM ISO Abbreviation: Cancers (Basel) Subsets: PubMed not MEDLINE
Subject
Language
English
ISSN
2072-6694
Abstract
Patients with advanced endometrial cancer (EC) show poor outcomes. Thus, the development of new therapeutic approaches to prevent metastasis development in high-risk patients is an unmet need. CXCR4 is overexpressed in EC tumor tissue, epitomizing an unexploited therapeutic target for this malignancy. The in vitro antitumor activity of two CXCR4-targeted nanoparticles, including either the C. diphtheriae (T22-DITOX-H6) or P. aeruginosa (T22-PE24-H6) toxin, was evaluated using viability assays. Apoptotic activation was assessed by DAPI and caspase-3 and PARP cleavage in cell blocks. Both nanotoxins were repeatedly administrated to a subcutaneous EC mouse model, whereas T22-DITOX-H6 was also used in a highly metastatic EC orthotopic model. Tumor burden was assessed through bioluminescence, while metastatic foci and toxicity were studied using histological or immunohistochemical analysis. We found that both nanotoxins exerted a potent antitumor effect both in vitro and in vivo via apoptosis and extended the survival of nanotoxin-treated mice without inducing any off-target toxicity. Repeated T22-DITOX-H6 administration in the metastatic model induced a dramatic reduction in tumor burden while significantly blocking peritoneal, lung and liver metastasis without systemic toxicity. Both nanotoxins, but especially T22-DITOX-H6, represent a promising therapeutic alternative for EC patients that have a dismal prognosis and lack effective therapies.