{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T01:37:47Z","timestamp":1785893867483,"version":"3.56.0"},"reference-count":52,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,10,14]],"date-time":"2021-10-14T00:00:00Z","timestamp":1634169600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>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), \u0394\u03c8m, 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, \u03b1-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.<\/jats:p>","DOI":"10.3390\/antiox10101618","type":"journal-article","created":{"date-parts":[[2021,10,14]],"date-time":"2021-10-14T09:10:49Z","timestamp":1634202649000},"page":"1618","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["FRI-1 Is an Anti-Cancer Isoquinolinequinone That Inhibits the Mitochondrial Bioenergetics and Blocks Metabolic Shifts by Redox Disruption in Breast Cancer Cells"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3132-226X","authenticated-orcid":false,"given":"Miguel","family":"C\u00f3rdova-Delgado","sequence":"first","affiliation":[{"name":"Laboratorio de Plasticidad Metab\u00f3lica y Bioenerg\u00e9tica, Programa de Farmacolog\u00eda Molecular y Cl\u00ednica, Instituto de Ciencias Biom\u00e9dicas (ICBM), Facultad de Medicina, Universidad de Chile, Independencia 1027, Casilla 7, Santiago 8380453, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3944-3138","authenticated-orcid":false,"given":"Sebasti\u00e1n","family":"Fuentes-Retamal","sequence":"additional","affiliation":[{"name":"Laboratorio de Plasticidad Metab\u00f3lica y Bioenerg\u00e9tica, Programa de Farmacolog\u00eda Molecular y Cl\u00ednica, Instituto de Ciencias Biom\u00e9dicas (ICBM), Facultad de Medicina, Universidad de Chile, Independencia 1027, Casilla 7, Santiago 8380453, Chile"},{"name":"Network for Snake Venom Research and Drug Discovery, Santiago 7800003, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7024-003X","authenticated-orcid":false,"given":"Charlotte","family":"Palominos","sequence":"additional","affiliation":[{"name":"Laboratorio de Plasticidad Metab\u00f3lica y Bioenerg\u00e9tica, Programa de Farmacolog\u00eda Molecular y Cl\u00ednica, Instituto de Ciencias Biom\u00e9dicas (ICBM), Facultad de Medicina, Universidad de Chile, Independencia 1027, Casilla 7, Santiago 8380453, Chile"},{"name":"Network for Snake Venom Research and Drug Discovery, Santiago 7800003, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camila","family":"L\u00f3pez-Torres","sequence":"additional","affiliation":[{"name":"Laboratorio de Plasticidad Metab\u00f3lica y Bioenerg\u00e9tica, Programa de Farmacolog\u00eda Molecular y Cl\u00ednica, Instituto de Ciencias Biom\u00e9dicas (ICBM), Facultad de Medicina, Universidad de Chile, Independencia 1027, Casilla 7, Santiago 8380453, Chile"},{"name":"Network for Snake Venom Research and Drug Discovery, Santiago 7800003, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Guzm\u00e1n-Rivera","sequence":"additional","affiliation":[{"name":"Escuela de Qu\u00edmica y Farmacia, Facultad de Medicina, Universidad Andr\u00e9s Bello, Santiago 8370149, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2752-3966","authenticated-orcid":false,"given":"Oney","family":"Ram\u00edrez-Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Laboratory of Chemistry and Biochemistry, Campus Lillo, University of Ays\u00e9n, Eusebio Lillo 667, Coyhaique 5951537, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5082-9146","authenticated-orcid":false,"given":"Ramiro","family":"Araya-Maturana","sequence":"additional","affiliation":[{"name":"Network for Snake Venom Research and Drug Discovery, Santiago 7800003, Chile"},{"name":"Instituto de Qu\u00edmica de Recursos Naturales, Universidad de Talca, Casilla 747, Talca 3460000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8582-4399","authenticated-orcid":false,"given":"F\u00e9lix A.","family":"Urra","sequence":"additional","affiliation":[{"name":"Laboratorio de Plasticidad Metab\u00f3lica y Bioenerg\u00e9tica, Programa de Farmacolog\u00eda Molecular y Cl\u00ednica, Instituto de Ciencias Biom\u00e9dicas (ICBM), Facultad de Medicina, Universidad de Chile, Independencia 1027, Casilla 7, Santiago 8380453, Chile"},{"name":"Network for Snake Venom Research and Drug Discovery, Santiago 7800003, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"113632","DOI":"10.1016\/j.ejmech.2021.113632","article-title":"Recent advances of quinones as a privileged structure in drug discovery","volume":"223","author":"Zhang","year":"2021","journal-title":"Eur. 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