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...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-08-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/8/2279 |
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| author | Alexandra Thomas Abhilash Samykutty Jorge G. Gomez-Gutierrez Wenyuan Yin Michael E. Egger Molly McNally Phillip Chuong William M. MacCuaig Sabrin Albeituni Matthew Zeiderman Min Li Barish H. Edil William E. Grizzle Kelly M. McMasters Lacey R. McNally |
| author_facet | Alexandra Thomas Abhilash Samykutty Jorge G. Gomez-Gutierrez Wenyuan Yin Michael E. Egger Molly McNally Phillip Chuong William M. MacCuaig Sabrin Albeituni Matthew Zeiderman Min Li Barish H. Edil William E. Grizzle Kelly M. McMasters Lacey R. McNally |
| author_sort | Alexandra Thomas |
| collection | DOAJ |
| 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 <i>p</i> = 0.0016, <i>p</i> = 0.00004 and S2CP9 <i>p</i> = 0.0009, <i>p</i> = 0.0001). Actively targeted nanodelivered echinomycin resulted in significant survival increases compared to Gemzar (S2VP10 <i>p</i> = 0.0003, S2CP9 <i>p</i> = 0.0017) or echinomycin only (S2VP10 <i>p</i> = 0.0096, S2CP9 <i>p</i> = 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. |
| first_indexed | 2024-03-10T17:26:15Z |
| format | Article |
| id | doaj.art-4760634ca1df4f9489812a0659c31181 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T17:26:15Z |
| publishDate | 2020-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-4760634ca1df4f9489812a0659c311812023-11-20T10:09:19ZengMDPI AGCancers2072-66942020-08-01128227910.3390/cancers12082279Actively Targeted Nanodelivery of Echinomycin Induces Autophagy-Mediated Death in Chemoresistant Pancreatic Cancer In VivoAlexandra Thomas0Abhilash Samykutty1Jorge G. Gomez-Gutierrez2Wenyuan Yin3Michael E. Egger4Molly McNally5Phillip Chuong6William M. MacCuaig7Sabrin Albeituni8Matthew Zeiderman9Min Li10Barish H. Edil11William E. Grizzle12Kelly M. McMasters13Lacey R. McNally14Department of Hematology Oncology, Wake Forest Baptist Health, Winston-Salem, NC 27157, USAStephenson Cancer Center, University of Oklahoma, Oklahoma City, OK 73104, USADepartment of Surgery, University of Louisville, Louisville, KY 40202, USADepartment of Surgery, University of Louisville, Louisville, KY 40202, USADepartment of Surgery, University of Louisville, Louisville, KY 40202, USAStephenson Cancer Center, University of Oklahoma, Oklahoma City, OK 73104, USADepartment of Surgery, University of Louisville, Louisville, KY 40202, USAStephenson Cancer Center, University of Oklahoma, Oklahoma City, OK 73104, USADepartment of Cancer Predisposition, St. Jude Children’s Research Hospital, Memphis, TN 38105, USADepartment of Surgery, University of California Davis, Sacramento, CA 95616, USADepartment of Surgery, University of Oklahoma, Oklahoma City, OK 73104, USADepartment of Surgery, University of Oklahoma, Oklahoma City, OK 73104, USADepartment of Pathology, University of Alabama Birmingham, Birmingham, AL 35294, USADepartment of Surgery, University of Louisville, Louisville, KY 40202, USAStephenson Cancer Center, University of Oklahoma, Oklahoma City, OK 73104, USAPancreatic 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 <i>p</i> = 0.0016, <i>p</i> = 0.00004 and S2CP9 <i>p</i> = 0.0009, <i>p</i> = 0.0001). Actively targeted nanodelivered echinomycin resulted in significant survival increases compared to Gemzar (S2VP10 <i>p</i> = 0.0003, S2CP9 <i>p</i> = 0.0017) or echinomycin only (S2VP10 <i>p</i> = 0.0096, S2CP9 <i>p</i> = 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.https://www.mdpi.com/2072-6694/12/8/2279echinomycinautophagyautophagic cell deathactive targeted liposomepancreatic canceralternative cancer therapy |
| spellingShingle | Alexandra Thomas Abhilash Samykutty Jorge G. Gomez-Gutierrez Wenyuan Yin Michael E. Egger Molly McNally Phillip Chuong William M. MacCuaig Sabrin Albeituni Matthew Zeiderman Min Li Barish H. Edil William E. Grizzle Kelly M. McMasters Lacey R. McNally Actively Targeted Nanodelivery of Echinomycin Induces Autophagy-Mediated Death in Chemoresistant Pancreatic Cancer In Vivo Cancers echinomycin autophagy autophagic cell death active targeted liposome pancreatic cancer alternative cancer therapy |
| 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 | echinomycin autophagy autophagic cell death active targeted liposome pancreatic cancer alternative cancer therapy |
| url | https://www.mdpi.com/2072-6694/12/8/2279 |
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