Low dosage combination treatment with metformin and simvastatin inhibits obesity-promoted pancreatic cancer development in male KrasG12D mice
Abstract Pancreatic ductal adenocarcinoma (PDAC), a highly lethal disease with limited therapeutic options, may benefit from repurposing of FDA-approved drugs in preventive or interceptive strategies in high-risk populations. Previous animal studies demonstrated that the use of metformin and statins...
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Nature Portfolio
2023-09-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-43498-9 |
| _version_ | 1797559904609763328 |
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| author | Yaroslav Teper Linda Ye Richard T. Waldron Aurelia Lugea Xiaoying Sun James Sinnett-Smith Oscar J. Hines Stephen J. Pandol Enrique Rozengurt Guido Eibl |
| author_facet | Yaroslav Teper Linda Ye Richard T. Waldron Aurelia Lugea Xiaoying Sun James Sinnett-Smith Oscar J. Hines Stephen J. Pandol Enrique Rozengurt Guido Eibl |
| author_sort | Yaroslav Teper |
| collection | DOAJ |
| description | Abstract Pancreatic ductal adenocarcinoma (PDAC), a highly lethal disease with limited therapeutic options, may benefit from repurposing of FDA-approved drugs in preventive or interceptive strategies in high-risk populations. Previous animal studies demonstrated that the use of metformin and statins as single agents at relatively high doses restrained PDAC development. Here, four-week-old mice expressing KrasG12D in all pancreatic lineages (KC mice) and fed an obesogenic high fat, high calorie diet that promotes early PDAC development were randomized onto low dosage metformin, simvastatin, or both drugs in combination administered orally. Dual treatment attenuated weight gain, fibro-inflammation, and development of advanced PDAC precursor lesions (pancreatic intraepithelial neoplasia [PanIN]-3) in male KC mice, without significant effect in females or when administered individually. Dual-treated KC mice had reduced proliferation of PanIN cells and decreased transcriptional activity of the Hippo effectors, YAP and TAZ, which are important regulators of PDAC development. Metformin and simvastatin also synergistically inhibited colony formation of pancreatic cancer cells in vitro. Together, our data demonstrated that a combination of low doses of metformin and simvastatin inhibits PDAC development and imply that both drugs are promising agents for being tested in clinical trials for preventing pancreatic cancer progression. |
| first_indexed | 2024-03-10T17:51:48Z |
| format | Article |
| id | doaj.art-6608e1bba2a74358ac50303e509a41fb |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-10T17:51:48Z |
| publishDate | 2023-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-6608e1bba2a74358ac50303e509a41fb2023-11-20T09:19:54ZengNature PortfolioScientific Reports2045-23222023-09-0113111210.1038/s41598-023-43498-9Low dosage combination treatment with metformin and simvastatin inhibits obesity-promoted pancreatic cancer development in male KrasG12D miceYaroslav Teper0Linda Ye1Richard T. Waldron2Aurelia Lugea3Xiaoying Sun4James Sinnett-Smith5Oscar J. Hines6Stephen J. Pandol7Enrique Rozengurt8Guido Eibl9Department of Surgery, David Geffen School of Medicine, University of CaliforniaDepartment of Surgery, David Geffen School of Medicine, University of CaliforniaPancreatic Research Group, Department of Medicine, Cedars-Sinai Medical CenterPancreatic Research Group, Department of Medicine, Cedars-Sinai Medical CenterDepartment of Medicine, David Geffen School of Medicine, University of CaliforniaDepartment of Medicine, David Geffen School of Medicine, University of CaliforniaDepartment of Surgery, David Geffen School of Medicine, University of CaliforniaPancreatic Research Group, Department of Medicine, Cedars-Sinai Medical CenterDepartment of Medicine, David Geffen School of Medicine, University of CaliforniaDepartment of Surgery, David Geffen School of Medicine, University of CaliforniaAbstract Pancreatic ductal adenocarcinoma (PDAC), a highly lethal disease with limited therapeutic options, may benefit from repurposing of FDA-approved drugs in preventive or interceptive strategies in high-risk populations. Previous animal studies demonstrated that the use of metformin and statins as single agents at relatively high doses restrained PDAC development. Here, four-week-old mice expressing KrasG12D in all pancreatic lineages (KC mice) and fed an obesogenic high fat, high calorie diet that promotes early PDAC development were randomized onto low dosage metformin, simvastatin, or both drugs in combination administered orally. Dual treatment attenuated weight gain, fibro-inflammation, and development of advanced PDAC precursor lesions (pancreatic intraepithelial neoplasia [PanIN]-3) in male KC mice, without significant effect in females or when administered individually. Dual-treated KC mice had reduced proliferation of PanIN cells and decreased transcriptional activity of the Hippo effectors, YAP and TAZ, which are important regulators of PDAC development. Metformin and simvastatin also synergistically inhibited colony formation of pancreatic cancer cells in vitro. Together, our data demonstrated that a combination of low doses of metformin and simvastatin inhibits PDAC development and imply that both drugs are promising agents for being tested in clinical trials for preventing pancreatic cancer progression.https://doi.org/10.1038/s41598-023-43498-9 |
| spellingShingle | Yaroslav Teper Linda Ye Richard T. Waldron Aurelia Lugea Xiaoying Sun James Sinnett-Smith Oscar J. Hines Stephen J. Pandol Enrique Rozengurt Guido Eibl Low dosage combination treatment with metformin and simvastatin inhibits obesity-promoted pancreatic cancer development in male KrasG12D mice Scientific Reports |
| title | Low dosage combination treatment with metformin and simvastatin inhibits obesity-promoted pancreatic cancer development in male KrasG12D mice |
| title_full | Low dosage combination treatment with metformin and simvastatin inhibits obesity-promoted pancreatic cancer development in male KrasG12D mice |
| title_fullStr | Low dosage combination treatment with metformin and simvastatin inhibits obesity-promoted pancreatic cancer development in male KrasG12D mice |
| title_full_unstemmed | Low dosage combination treatment with metformin and simvastatin inhibits obesity-promoted pancreatic cancer development in male KrasG12D mice |
| title_short | Low dosage combination treatment with metformin and simvastatin inhibits obesity-promoted pancreatic cancer development in male KrasG12D mice |
| title_sort | low dosage combination treatment with metformin and simvastatin inhibits obesity promoted pancreatic cancer development in male krasg12d mice |
| url | https://doi.org/10.1038/s41598-023-43498-9 |
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