The Protease Inhibitor Amprenavir Protects against Pepsin-Induced Esophageal Epithelial Barrier Disruption and Cancer-Associated Changes
Gastroesophageal reflux disease (GERD) significantly impacts patient quality of life and is a major risk factor for the development of Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC). Proton pump inhibitors (PPIs) are the standard-of-care for GERD and are among the most prescribed drugs...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-04-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/7/6765 |
| _version_ | 1797607777958363136 |
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| author | Simon Blaine-Sauer Tina L. Samuels Ke Yan Nikki Johnston |
| author_facet | Simon Blaine-Sauer Tina L. Samuels Ke Yan Nikki Johnston |
| author_sort | Simon Blaine-Sauer |
| collection | DOAJ |
| description | Gastroesophageal reflux disease (GERD) significantly impacts patient quality of life and is a major risk factor for the development of Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC). Proton pump inhibitors (PPIs) are the standard-of-care for GERD and are among the most prescribed drugs in the world, but do not protect against nonacid components of reflux such as pepsin, or prevent reflux-associated carcinogenesis. We recently identified an HIV protease inhibitor amprenavir that inhibits pepsin and demonstrated the antireflux therapeutic potential of its prodrug fosamprenavir in a mouse model of laryngopharyngeal reflux. In this study, we assessed the capacity of amprenavir to protect against esophageal epithelial barrier disruption in vitro and related molecular events, E-cadherin cleavage, and matrix metalloproteinase induction, which are associated with GERD severity and esophageal cancer. Herein, weakly acidified pepsin (though not acid alone) caused cell dissociation accompanied by regulated intramembrane proteolysis of E-cadherin. Soluble E-cadherin responsive matrix metalloproteinases (MMPs) were transcriptionally upregulated 24 h post-treatment. Amprenavir, at serum concentrations achievable given the manufacturer-recommended dose of fosamprenavir, protected against pepsin-induced cell dissociation, E-cadherin cleavage, and MMP induction. These results support a potential therapeutic role for amprenavir in GERD recalcitrant to PPI therapy and for preventing GERD-associated neoplastic changes. |
| first_indexed | 2024-03-11T05:34:28Z |
| format | Article |
| id | doaj.art-fefe4118c8d2451289c0a23798f42e53 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T05:34:28Z |
| publishDate | 2023-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-fefe4118c8d2451289c0a23798f42e532023-11-17T16:55:43ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-04-01247676510.3390/ijms24076765The Protease Inhibitor Amprenavir Protects against Pepsin-Induced Esophageal Epithelial Barrier Disruption and Cancer-Associated ChangesSimon Blaine-Sauer0Tina L. Samuels1Ke Yan2Nikki Johnston3Department of Otolaryngology and Communication Science, Medical College of Wisconsin, Milwaukee, WI 53226, USADepartment of Otolaryngology and Communication Science, Medical College of Wisconsin, Milwaukee, WI 53226, USADepartment of Pediatrics Quantitative Health Sciences, Medical College of Wisconsin, Milwaukee, WI 53226, USADepartment of Otolaryngology and Communication Science, Medical College of Wisconsin, Milwaukee, WI 53226, USAGastroesophageal reflux disease (GERD) significantly impacts patient quality of life and is a major risk factor for the development of Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC). Proton pump inhibitors (PPIs) are the standard-of-care for GERD and are among the most prescribed drugs in the world, but do not protect against nonacid components of reflux such as pepsin, or prevent reflux-associated carcinogenesis. We recently identified an HIV protease inhibitor amprenavir that inhibits pepsin and demonstrated the antireflux therapeutic potential of its prodrug fosamprenavir in a mouse model of laryngopharyngeal reflux. In this study, we assessed the capacity of amprenavir to protect against esophageal epithelial barrier disruption in vitro and related molecular events, E-cadherin cleavage, and matrix metalloproteinase induction, which are associated with GERD severity and esophageal cancer. Herein, weakly acidified pepsin (though not acid alone) caused cell dissociation accompanied by regulated intramembrane proteolysis of E-cadherin. Soluble E-cadherin responsive matrix metalloproteinases (MMPs) were transcriptionally upregulated 24 h post-treatment. Amprenavir, at serum concentrations achievable given the manufacturer-recommended dose of fosamprenavir, protected against pepsin-induced cell dissociation, E-cadherin cleavage, and MMP induction. These results support a potential therapeutic role for amprenavir in GERD recalcitrant to PPI therapy and for preventing GERD-associated neoplastic changes.https://www.mdpi.com/1422-0067/24/7/6765gastroesophageal reflux diseaseantireflux therapeuticspepsinamprenavirfosamprenavirprotease inhibitors |
| spellingShingle | Simon Blaine-Sauer Tina L. Samuels Ke Yan Nikki Johnston The Protease Inhibitor Amprenavir Protects against Pepsin-Induced Esophageal Epithelial Barrier Disruption and Cancer-Associated Changes International Journal of Molecular Sciences gastroesophageal reflux disease antireflux therapeutics pepsin amprenavir fosamprenavir protease inhibitors |
| title | The Protease Inhibitor Amprenavir Protects against Pepsin-Induced Esophageal Epithelial Barrier Disruption and Cancer-Associated Changes |
| title_full | The Protease Inhibitor Amprenavir Protects against Pepsin-Induced Esophageal Epithelial Barrier Disruption and Cancer-Associated Changes |
| title_fullStr | The Protease Inhibitor Amprenavir Protects against Pepsin-Induced Esophageal Epithelial Barrier Disruption and Cancer-Associated Changes |
| title_full_unstemmed | The Protease Inhibitor Amprenavir Protects against Pepsin-Induced Esophageal Epithelial Barrier Disruption and Cancer-Associated Changes |
| title_short | The Protease Inhibitor Amprenavir Protects against Pepsin-Induced Esophageal Epithelial Barrier Disruption and Cancer-Associated Changes |
| title_sort | protease inhibitor amprenavir protects against pepsin induced esophageal epithelial barrier disruption and cancer associated changes |
| topic | gastroesophageal reflux disease antireflux therapeutics pepsin amprenavir fosamprenavir protease inhibitors |
| url | https://www.mdpi.com/1422-0067/24/7/6765 |
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