FRI-1 Is an Anti-Cancer Isoquinolinequinone That Inhibits the Mitochondrial Bioenergetics and Blocks Metabolic Shifts by Redox Disruption in Breast Cancer Cells
Abstract
:1. Introduction
2. Materials and Methods
2.1. Chemical and Reagents
2.2. Chemistry
2.2.1. Synthesis of Octyl and Methyl 1,3-Dimethyl-5,8-dioxo-5,8-dihydroisoquinoline-4-carboxylates (FRI-1 and FRI-3)
2.2.2. Synthesis of Octyl 1,3-Dimethyl-5,8-dioxo-5,8-dihydroisoquinoline-4-carboxylate (FRI-3)
2.3. Breast Cell Lines
2.4. Measurement of Mitochondrial Membrane Potential (Δψm)
2.5. Clonogenic Assay
2.6. Cellular Respiration in Real-Time
2.7. Respiration in Isolated Mitochondria
2.8. Mitochondrial ROS (mtROS) Levels
2.9. NAD(P)H and ATP Levels
2.10. Cell Death Assay
2.11. MTT Assay
2.12. Western Blotting
2.13. Statistical Analysis
3. Results
3.1. FRI-1 Inhibits Cell Proliferation, Clonogenic Capacity, and Induces Apoptosis in Breast Cancer Cells
3.2. FRI-1 Inhibits Mitochondrial Respiration and Blocks Metabolic Remodeling under Energetic Stress in Breast Cancer Cells
3.3. FRI-1 Produces Inhibition of Mitochondrial Bioenergetics and Redox Stress in Breast Cancer Cells
3.4. FRI-1 Increases Oxygen Consumption Rate in Tumor Mitochondria
3.5. FRI-1 Induces a Pro-Survival AMPK Signaling in BC Cells
3.6. FRI-1-Induced BC Cell Death Is Prevented by Dimethyl-aKG and Sensitized by Lipoic Acid or CPI-613 Combination
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Córdova-Delgado, M.; Fuentes-Retamal, S.; Palominos, C.; López-Torres, C.; Guzmán-Rivera, D.; Ramírez-Rodríguez, O.; Araya-Maturana, R.; Urra, F.A. FRI-1 Is an Anti-Cancer Isoquinolinequinone That Inhibits the Mitochondrial Bioenergetics and Blocks Metabolic Shifts by Redox Disruption in Breast Cancer Cells. Antioxidants 2021, 10, 1618. https://doi.org/10.3390/antiox10101618
Córdova-Delgado M, Fuentes-Retamal S, Palominos C, López-Torres C, Guzmán-Rivera D, Ramírez-Rodríguez O, Araya-Maturana R, Urra FA. FRI-1 Is an Anti-Cancer Isoquinolinequinone That Inhibits the Mitochondrial Bioenergetics and Blocks Metabolic Shifts by Redox Disruption in Breast Cancer Cells. Antioxidants. 2021; 10(10):1618. https://doi.org/10.3390/antiox10101618
Chicago/Turabian StyleCórdova-Delgado, Miguel, Sebastián Fuentes-Retamal, Charlotte Palominos, Camila López-Torres, Daniela Guzmán-Rivera, Oney Ramírez-Rodríguez, Ramiro Araya-Maturana, and Félix A. Urra. 2021. "FRI-1 Is an Anti-Cancer Isoquinolinequinone That Inhibits the Mitochondrial Bioenergetics and Blocks Metabolic Shifts by Redox Disruption in Breast Cancer Cells" Antioxidants 10, no. 10: 1618. https://doi.org/10.3390/antiox10101618