Fri-1 is an anti-cancer isoquinolinequinone that inhibits the mitochondrial bioenergetics and blocks metabolic shifts by redox disruption in breast cancer cells
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Fecha
2021-10
Profesor/a Guía
Facultad/escuela
Idioma
es
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MDPI
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Licencia CC
Attribution 4.0 International
CC BY 4.0
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Licencia CC
https://creativecommons.org/licenses/by/4.0/
Resumen
Since breast cancer (BC) cells are dependent on mitochondrial bioenergetics for promoting proliferation, survival, and metastasis, mitochondria highlight as an important target for anticancer drug discovery. FRI-1, methyl 1, 3-dimethyl-5, 8-dioxo-5, 8-dihydro-4-isoquinolinecarboxylate, was previously described as a selective cytotoxic compound on cancer cell lines, however, details on the mechanism of action remain unknown. In this work, we describe that FRI-1 inhibits mitochondrial bioenergetics, producing apoptosis in MCF7 and MDA-MB-231 BC cell lines. FRI-1 decreases the maximal oxygen consumption rate (OCR), ∆ψm, NADH, and ATP levels, with a notable increase of mitochondrial reactive oxygen species (ROS) production, promoting AMPK activation with pro-survival effects. Moreover, FRI-1 inhibits the metabolic remodeling to glycolysis induced by oligomycin. In isolated tumoral mitochondria, FRI-1 increases Complex I and III-dependent OCR state 2, and this is sensitive to rotenone and antimycin A inhibitor additions, suggesting a redox cycling event. Remarkably, α-ketoglutarate and lipoic acid supplementation reversed and promoted, respectively, the FRI-1-induced apoptosis, suggesting that mitochondrial redox disruption affects 2-oxoglutarate dehydrogenase (OGDH) activity, and this is involved in their anticancer mechanism. Consistent with this, the combination of FRI-1 and CPI-613, a dual inhibitor of redox-sensible tricarboxylic acid (TCA) cycle enzymes PDH and OGDH, produced extensive BC cell death. Taken together, our results suggest that FRI-1 exhibits anticancer effects through inhibition of mitochondrial bioenergetics by redox disruption in BC cells. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
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Indexación: Scopus.
Palabras clave
2-oxoglutarate dehydrogenase (OGDH), AMP-activated kinase (AMPK) signaling, CPI-613, Devimistat, Mitocans, Mitochondria, Tricarboxylic acid (TCA) cycle
Citación
Antioxidants, Volume 10, Issue 10, October 2021, Article number 1618
DOI
10.3390/antiox10101618