Metformin Inhibits Migration and Invasion by Suppressing ROS Production and COX2 Expression in MDA-MB-231 Breast Cancer Cells
Background: Several mechanisms of action have been proposed to explain the apparent antineoplastic functions of metformin, many of which are observed at high concentrations that may not be reflective of achievable tissue concentrations. We propose that metformin at low concentrations functions to in...
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| Format: | Article |
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MDPI AG
2018-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/19/11/3692 |
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| author | Chandler Schexnayder Kiera Broussard Demitrius Onuaguluchi Anthony Poché Moamen Ismail LeFontae McAtee Shawn Llopis Amber Keizerweerd Harris McFerrin Christopher Williams |
| author_facet | Chandler Schexnayder Kiera Broussard Demitrius Onuaguluchi Anthony Poché Moamen Ismail LeFontae McAtee Shawn Llopis Amber Keizerweerd Harris McFerrin Christopher Williams |
| author_sort | Chandler Schexnayder |
| collection | DOAJ |
| description | Background: Several mechanisms of action have been proposed to explain the apparent antineoplastic functions of metformin, many of which are observed at high concentrations that may not be reflective of achievable tissue concentrations. We propose that metformin at low concentrations functions to inhibit ROS production and inflammatory signaling in breast cancer, thereby reducing metastasis. Methods: Using the highly invasive MDA-MB-231 breast carcinoma model, we ascertained the impact of metformin on cell viability by DNA content analysis and fluorescent dye exclusion. Migration and invasion assays were performed using a modified Boyden chamber assay and metastasis was ascertained using the chorioallantoic membrane (CAM) assay. PGE2 production was measured by Enzyme-Linked Immunosorbent Assay (ELISA). COX2 and ICAM1 levels were determined by flow cytometry immunoassay. Results: Metformin acutely decreased cell viability and caused G2 cell cycle arrest only at high concentrations (10 mM). At 100 µM, however, metformin reduced ICAM1 and COX2 expression, as well as reduced PGE2 production and endogenous mitochondrial ROS production while failing to significantly impact cell viability. Consequently, metformin inhibited migration, invasion in vitro and PGE2-dependent metastasis in CAM assays. Conclusion: At pharmacologically achievable concentrations, metformin does not drastically impact cell viability, but inhibits inflammatory signaling and metastatic progression in breast cancer cells. |
| first_indexed | 2024-04-12T21:42:17Z |
| format | Article |
| id | doaj.art-a30513887b584a7786524b010873233f |
| institution | Directory Open Access Journal |
| issn | 1422-0067 |
| language | English |
| last_indexed | 2024-04-12T21:42:17Z |
| publishDate | 2018-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-a30513887b584a7786524b010873233f2022-12-22T03:15:44ZengMDPI AGInternational Journal of Molecular Sciences1422-00672018-11-011911369210.3390/ijms19113692ijms19113692Metformin Inhibits Migration and Invasion by Suppressing ROS Production and COX2 Expression in MDA-MB-231 Breast Cancer CellsChandler Schexnayder0Kiera Broussard1Demitrius Onuaguluchi2Anthony Poché3Moamen Ismail4LeFontae McAtee5Shawn Llopis6Amber Keizerweerd7Harris McFerrin8Christopher Williams9College of Pharmacy, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USACollege of Pharmacy, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USACollege of Pharmacy, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USACollege of Pharmacy, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USADepartment of Biology, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USACollege of Pharmacy, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USACollege of Pharmacy, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USACollege of Pharmacy, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USADepartment of Biology, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USACollege of Pharmacy, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USABackground: Several mechanisms of action have been proposed to explain the apparent antineoplastic functions of metformin, many of which are observed at high concentrations that may not be reflective of achievable tissue concentrations. We propose that metformin at low concentrations functions to inhibit ROS production and inflammatory signaling in breast cancer, thereby reducing metastasis. Methods: Using the highly invasive MDA-MB-231 breast carcinoma model, we ascertained the impact of metformin on cell viability by DNA content analysis and fluorescent dye exclusion. Migration and invasion assays were performed using a modified Boyden chamber assay and metastasis was ascertained using the chorioallantoic membrane (CAM) assay. PGE2 production was measured by Enzyme-Linked Immunosorbent Assay (ELISA). COX2 and ICAM1 levels were determined by flow cytometry immunoassay. Results: Metformin acutely decreased cell viability and caused G2 cell cycle arrest only at high concentrations (10 mM). At 100 µM, however, metformin reduced ICAM1 and COX2 expression, as well as reduced PGE2 production and endogenous mitochondrial ROS production while failing to significantly impact cell viability. Consequently, metformin inhibited migration, invasion in vitro and PGE2-dependent metastasis in CAM assays. Conclusion: At pharmacologically achievable concentrations, metformin does not drastically impact cell viability, but inhibits inflammatory signaling and metastatic progression in breast cancer cells.https://www.mdpi.com/1422-0067/19/11/3692metforminICAM1metastasisreactive oxygen speciesCOX2 |
| spellingShingle | Chandler Schexnayder Kiera Broussard Demitrius Onuaguluchi Anthony Poché Moamen Ismail LeFontae McAtee Shawn Llopis Amber Keizerweerd Harris McFerrin Christopher Williams Metformin Inhibits Migration and Invasion by Suppressing ROS Production and COX2 Expression in MDA-MB-231 Breast Cancer Cells International Journal of Molecular Sciences metformin ICAM1 metastasis reactive oxygen species COX2 |
| title | Metformin Inhibits Migration and Invasion by Suppressing ROS Production and COX2 Expression in MDA-MB-231 Breast Cancer Cells |
| title_full | Metformin Inhibits Migration and Invasion by Suppressing ROS Production and COX2 Expression in MDA-MB-231 Breast Cancer Cells |
| title_fullStr | Metformin Inhibits Migration and Invasion by Suppressing ROS Production and COX2 Expression in MDA-MB-231 Breast Cancer Cells |
| title_full_unstemmed | Metformin Inhibits Migration and Invasion by Suppressing ROS Production and COX2 Expression in MDA-MB-231 Breast Cancer Cells |
| title_short | Metformin Inhibits Migration and Invasion by Suppressing ROS Production and COX2 Expression in MDA-MB-231 Breast Cancer Cells |
| title_sort | metformin inhibits migration and invasion by suppressing ros production and cox2 expression in mda mb 231 breast cancer cells |
| topic | metformin ICAM1 metastasis reactive oxygen species COX2 |
| url | https://www.mdpi.com/1422-0067/19/11/3692 |
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