Efficacy of Providing the PI3K p110α Inhibitor BYL719 (Alpelisib) to Middle-Aged Mice in Their Diet
BYL719 (alpelisib) is a small molecule inhibitor of PI3K p110α developed for cancer therapy. Targeted suppression of PI3K has led to lifespan extension in rodents and model organisms. If PI3K inhibitors are to be considered as an aging therapeutic, it is important to understand the potential consequ...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-01-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/11/2/150 |
| _version_ | 1797407874013462528 |
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| author | Christopher P. Hedges Jordi Boix Jagdish K. Jaiswal Bhoopika Shetty Peter R. Shepherd Troy L. Merry |
| author_facet | Christopher P. Hedges Jordi Boix Jagdish K. Jaiswal Bhoopika Shetty Peter R. Shepherd Troy L. Merry |
| author_sort | Christopher P. Hedges |
| collection | DOAJ |
| description | BYL719 (alpelisib) is a small molecule inhibitor of PI3K p110α developed for cancer therapy. Targeted suppression of PI3K has led to lifespan extension in rodents and model organisms. If PI3K inhibitors are to be considered as an aging therapeutic, it is important to understand the potential consequences of long-term exposure, and the most practical way to achieve this is through diet administration. Here, we investigated the pharmacokinetics of BYL719 delivered in diet and the efficacy of BYL719 to suppress insulin signaling when administered in the diet of 8-month-old male and female mice. Compared to oral gavage, diet incorporation resulted in a lower peak plasma BYL719 (3.6 vs. 9.2 μM) concentration but similar half-life (~1.5 h). Consuming BYL719 resulted in decreased insulin signaling in liver and muscle within 72 h, and mice still showed impaired glucose tolerance and insulin sensitivity following 6 weeks of access to a diet containing 0.3 g/kg BYL719. However, consuming BYL719 did not affect food intake, body mass, muscle function (rotarod and hang time performance) or cognitive behaviors. This provides evidence that BYL719 has long-term efficacy without major toxicity or side effects, and suggests that administering BYL719 in diet is suitable for studying the effect of pharmacological suppression of PI3K p110α on aging and metabolic function. |
| first_indexed | 2024-03-09T03:47:59Z |
| format | Article |
| id | doaj.art-fb625d826df24446bf6da1359a25b651 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-09T03:47:59Z |
| publishDate | 2021-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-fb625d826df24446bf6da1359a25b6512023-12-03T14:32:19ZengMDPI AGBiomolecules2218-273X2021-01-0111215010.3390/biom11020150Efficacy of Providing the PI3K p110α Inhibitor BYL719 (Alpelisib) to Middle-Aged Mice in Their DietChristopher P. Hedges0Jordi Boix1Jagdish K. Jaiswal2Bhoopika Shetty3Peter R. Shepherd4Troy L. Merry5Discipline of Nutrition, School of Medical Sciences, University of Auckland, Auckland 1023, New ZealandCentre for Brain Research, University of Auckland, Auckland 1023, New ZealandMaurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland 1023, New ZealandDiscipline of Nutrition, School of Medical Sciences, University of Auckland, Auckland 1023, New ZealandMaurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland 1023, New ZealandDiscipline of Nutrition, School of Medical Sciences, University of Auckland, Auckland 1023, New ZealandBYL719 (alpelisib) is a small molecule inhibitor of PI3K p110α developed for cancer therapy. Targeted suppression of PI3K has led to lifespan extension in rodents and model organisms. If PI3K inhibitors are to be considered as an aging therapeutic, it is important to understand the potential consequences of long-term exposure, and the most practical way to achieve this is through diet administration. Here, we investigated the pharmacokinetics of BYL719 delivered in diet and the efficacy of BYL719 to suppress insulin signaling when administered in the diet of 8-month-old male and female mice. Compared to oral gavage, diet incorporation resulted in a lower peak plasma BYL719 (3.6 vs. 9.2 μM) concentration but similar half-life (~1.5 h). Consuming BYL719 resulted in decreased insulin signaling in liver and muscle within 72 h, and mice still showed impaired glucose tolerance and insulin sensitivity following 6 weeks of access to a diet containing 0.3 g/kg BYL719. However, consuming BYL719 did not affect food intake, body mass, muscle function (rotarod and hang time performance) or cognitive behaviors. This provides evidence that BYL719 has long-term efficacy without major toxicity or side effects, and suggests that administering BYL719 in diet is suitable for studying the effect of pharmacological suppression of PI3K p110α on aging and metabolic function.https://www.mdpi.com/2218-273X/11/2/150insulin signalingagingBYL-719glucose tolerancepharmacokinetics |
| spellingShingle | Christopher P. Hedges Jordi Boix Jagdish K. Jaiswal Bhoopika Shetty Peter R. Shepherd Troy L. Merry Efficacy of Providing the PI3K p110α Inhibitor BYL719 (Alpelisib) to Middle-Aged Mice in Their Diet Biomolecules insulin signaling aging BYL-719 glucose tolerance pharmacokinetics |
| title | Efficacy of Providing the PI3K p110α Inhibitor BYL719 (Alpelisib) to Middle-Aged Mice in Their Diet |
| title_full | Efficacy of Providing the PI3K p110α Inhibitor BYL719 (Alpelisib) to Middle-Aged Mice in Their Diet |
| title_fullStr | Efficacy of Providing the PI3K p110α Inhibitor BYL719 (Alpelisib) to Middle-Aged Mice in Their Diet |
| title_full_unstemmed | Efficacy of Providing the PI3K p110α Inhibitor BYL719 (Alpelisib) to Middle-Aged Mice in Their Diet |
| title_short | Efficacy of Providing the PI3K p110α Inhibitor BYL719 (Alpelisib) to Middle-Aged Mice in Their Diet |
| title_sort | efficacy of providing the pi3k p110α inhibitor byl719 alpelisib to middle aged mice in their diet |
| topic | insulin signaling aging BYL-719 glucose tolerance pharmacokinetics |
| url | https://www.mdpi.com/2218-273X/11/2/150 |
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