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Actively Targeted Nanodelivery of Echinomycin Induces Autophagy-Mediated Death in Chemoresistant Pancreatic Cancer In Vivo

Pancreatic cancer remains a recalcitrant neoplasm associated with chemoresistance and high fatality. Because it is frequently resistant to apoptosis, exploiting autophagic cell death could offer a new treatment approach. We repurpose echinomycin, an antibiotic encapsulated within a syndecan-1 active...

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Autores principales: Thomas, Alexandra, Samykutty, Abhilash, Gomez-Gutierrez, Jorge G., Yin, Wenyuan, Egger, Michael E., McNally, Molly, Chuong, Phillip, MacCuaig, William M., Albeituni, Sabrin, Zeiderman, Matthew, Li, Min, Edil, Barish H., Grizzle, William E., McMasters, Kelly M., McNally, Lacey R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464900/
https://www.ncbi.nlm.nih.gov/pubmed/32823919
http://dx.doi.org/10.3390/cancers12082279
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author Thomas, Alexandra
Samykutty, Abhilash
Gomez-Gutierrez, Jorge G.
Yin, Wenyuan
Egger, Michael E.
McNally, Molly
Chuong, Phillip
MacCuaig, William M.
Albeituni, Sabrin
Zeiderman, Matthew
Li, Min
Edil, Barish H.
Grizzle, William E.
McMasters, Kelly M.
McNally, Lacey R.
author_facet Thomas, Alexandra
Samykutty, Abhilash
Gomez-Gutierrez, Jorge G.
Yin, Wenyuan
Egger, Michael E.
McNally, Molly
Chuong, Phillip
MacCuaig, William M.
Albeituni, Sabrin
Zeiderman, Matthew
Li, Min
Edil, Barish H.
Grizzle, William E.
McMasters, Kelly M.
McNally, Lacey R.
author_sort Thomas, Alexandra
collection PubMed
description Pancreatic cancer remains a recalcitrant neoplasm associated with chemoresistance and high fatality. Because it is frequently resistant to apoptosis, exploiting autophagic cell death could offer a new treatment approach. We repurpose echinomycin, an antibiotic encapsulated within a syndecan-1 actively targeted nanoparticle, for treatment of pancreatic cancer. Tumor-specific uptake, biodistribution, efficacy of nanodelivered echinomycin, and mechanism of cell death were assessed in aggressive, metastatic models of pancreatic cancer. In these autophagic-dependent pancreatic cancer models, echinomycin treatment resulted in autophagic cell death noted by high levels of LC3 among other autophagy markers, but without hallmarks of apoptosis, e.g., caspase activation and chromatin fragmentation, or necrosis, e.g., plasma membrane degradation and chromatin condensation/degrading. In vivo, biodistribution of syndecan-1-targeted nanoparticles indicated preferential S2VP10 or S2CP9 tumor uptake compared to the liver and kidney (S2VP10 p = 0.0016, p = 0.00004 and S2CP9 p = 0.0009, p = 0.0001). Actively targeted nanodelivered echinomycin resulted in significant survival increases compared to Gemzar (S2VP10 p = 0.0003, S2CP9 p = 0.0017) or echinomycin only (S2VP10 p = 0.0096, S2CP9 p = 0.0073). We demonstrate that actively targeted nanodelivery of echinomycin results in autophagic cell death in pancreatic and potentially other high-autophagy, apoptosis-resistant tumors. Collectively, these findings support syndecan-1-targeted delivery of echinomycin and dysregulation of autophagy to induce cell death in pancreatic cancer.
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spelling pubmed-74649002020-09-04 Actively Targeted Nanodelivery of Echinomycin Induces Autophagy-Mediated Death in Chemoresistant Pancreatic Cancer In Vivo Thomas, Alexandra Samykutty, Abhilash Gomez-Gutierrez, Jorge G. Yin, Wenyuan Egger, Michael E. McNally, Molly Chuong, Phillip MacCuaig, William M. Albeituni, Sabrin Zeiderman, Matthew Li, Min Edil, Barish H. Grizzle, William E. McMasters, Kelly M. McNally, Lacey R. Cancers (Basel) Article Pancreatic cancer remains a recalcitrant neoplasm associated with chemoresistance and high fatality. Because it is frequently resistant to apoptosis, exploiting autophagic cell death could offer a new treatment approach. We repurpose echinomycin, an antibiotic encapsulated within a syndecan-1 actively targeted nanoparticle, for treatment of pancreatic cancer. Tumor-specific uptake, biodistribution, efficacy of nanodelivered echinomycin, and mechanism of cell death were assessed in aggressive, metastatic models of pancreatic cancer. In these autophagic-dependent pancreatic cancer models, echinomycin treatment resulted in autophagic cell death noted by high levels of LC3 among other autophagy markers, but without hallmarks of apoptosis, e.g., caspase activation and chromatin fragmentation, or necrosis, e.g., plasma membrane degradation and chromatin condensation/degrading. In vivo, biodistribution of syndecan-1-targeted nanoparticles indicated preferential S2VP10 or S2CP9 tumor uptake compared to the liver and kidney (S2VP10 p = 0.0016, p = 0.00004 and S2CP9 p = 0.0009, p = 0.0001). Actively targeted nanodelivered echinomycin resulted in significant survival increases compared to Gemzar (S2VP10 p = 0.0003, S2CP9 p = 0.0017) or echinomycin only (S2VP10 p = 0.0096, S2CP9 p = 0.0073). We demonstrate that actively targeted nanodelivery of echinomycin results in autophagic cell death in pancreatic and potentially other high-autophagy, apoptosis-resistant tumors. Collectively, these findings support syndecan-1-targeted delivery of echinomycin and dysregulation of autophagy to induce cell death in pancreatic cancer. MDPI 2020-08-14 /pmc/articles/PMC7464900/ /pubmed/32823919 http://dx.doi.org/10.3390/cancers12082279 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Thomas, Alexandra
Samykutty, Abhilash
Gomez-Gutierrez, Jorge G.
Yin, Wenyuan
Egger, Michael E.
McNally, Molly
Chuong, Phillip
MacCuaig, William M.
Albeituni, Sabrin
Zeiderman, Matthew
Li, Min
Edil, Barish H.
Grizzle, William E.
McMasters, Kelly M.
McNally, Lacey R.
Actively Targeted Nanodelivery of Echinomycin Induces Autophagy-Mediated Death in Chemoresistant Pancreatic Cancer In Vivo
title Actively Targeted Nanodelivery of Echinomycin Induces Autophagy-Mediated Death in Chemoresistant Pancreatic Cancer In Vivo
title_full Actively Targeted Nanodelivery of Echinomycin Induces Autophagy-Mediated Death in Chemoresistant Pancreatic Cancer In Vivo
title_fullStr Actively Targeted Nanodelivery of Echinomycin Induces Autophagy-Mediated Death in Chemoresistant Pancreatic Cancer In Vivo
title_full_unstemmed Actively Targeted Nanodelivery of Echinomycin Induces Autophagy-Mediated Death in Chemoresistant Pancreatic Cancer In Vivo
title_short Actively Targeted Nanodelivery of Echinomycin Induces Autophagy-Mediated Death in Chemoresistant Pancreatic Cancer In Vivo
title_sort actively targeted nanodelivery of echinomycin induces autophagy-mediated death in chemoresistant pancreatic cancer in vivo
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464900/
https://www.ncbi.nlm.nih.gov/pubmed/32823919
http://dx.doi.org/10.3390/cancers12082279
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