{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T15:09:54Z","timestamp":1787238594839,"version":"build-2736575974"},"reference-count":76,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,8,10]],"date-time":"2023-08-10T00:00:00Z","timestamp":1691625600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002848","name":"Agencia Nacional de Investigaci\u00f3n y Desarrollo","doi-asserted-by":"publisher","award":["FONDECYT-11201322"],"award-info":[{"award-number":["FONDECYT-11201322"]}],"id":[{"id":"10.13039\/501100002848","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002848","name":"Agencia Nacional de Investigaci\u00f3n y Desarrollo","doi-asserted-by":"publisher","award":["FONDECYT-1221874"],"award-info":[{"award-number":["FONDECYT-1221874"]}],"id":[{"id":"10.13039\/501100002848","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002848","name":"Agencia Nacional de Investigaci\u00f3n y Desarrollo","doi-asserted-by":"publisher","award":["FONDECYT-1221848"],"award-info":[{"award-number":["FONDECYT-1221848"]}],"id":[{"id":"10.13039\/501100002848","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002848","name":"Agencia Nacional de Investigaci\u00f3n y Desarrollo","doi-asserted-by":"publisher","award":["FONDEQUIP EQM220164"],"award-info":[{"award-number":["FONDEQUIP EQM220164"]}],"id":[{"id":"10.13039\/501100002848","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002848","name":"Agencia Nacional de Investigaci\u00f3n y Desarrollo","doi-asserted-by":"publisher","award":["VID-UChile UM-03\/22"],"award-info":[{"award-number":["VID-UChile UM-03\/22"]}],"id":[{"id":"10.13039\/501100002848","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Mitochondrial Complex I plays a crucial role in the proliferation, chemoresistance, and metastasis of breast cancer (BC) cells. This highlights it as an attractive target for anti-cancer drugs. Using submitochondrial particles, we identified FRV\u20131, an ortho-carbonyl quinone, which inhibits NADH:duroquinone activity in D-active conformation and reduces the 3ADP state respiration dependent on Complex I, causing mitochondrial depolarization, ATP drop, increased superoxide levels, and metabolic remodeling towards glycolysis in BC cells. Introducing methyl groups at FRV\u20131 structure produced analogs that acted as electron acceptors at the Complex I level or increased the inhibitory effect of FCCP-stimulated oxygen consumption rate, which correlated with their redox potential, but increased toxicity on RMF-621 human breast fibroblasts was observed. FRV\u20131 was inactive in the naphthoquinone oxidoreductase 1 (NOQ1)-positive BC cell line, MCF7, but the sensitivity was recovered by dicoumarol, a NOQ1 inhibitor, suggesting that FRV\u20131 is a NOQ1 substrate. Importantly, FRV\u20131 selectively inhibited the proliferation, migration, and invasion of NQO1 negative BC cell, MDA-MB-231, in an OXPHOS- and ROS-dependent manner and sensitized it to the BH3 mimetic drug venetoclax. Overall, FRV\u20131 is a novel Complex I inhibitor in D-active conformation, blocking possibly the re-activation to A-state, producing selective anti-cancer effects in NQO1-negative BC cell lines.<\/jats:p>","DOI":"10.3390\/antiox12081597","type":"journal-article","created":{"date-parts":[[2023,8,11]],"date-time":"2023-08-11T10:20:16Z","timestamp":1691749216000},"page":"1597","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["A New Quinone-Based Inhibitor of Mitochondrial Complex I in D-Conformation, Producing Invasion Reduction and Sensitization to Venetoclax in Breast Cancer Cells"],"prefix":"10.3390","volume":"12","author":[{"given":"Mat\u00edas","family":"Monroy-C\u00e1rdenas","sequence":"first","affiliation":[{"name":"Interdisciplinary Group on Mitochondrial Targeting and Bioenergetics (MIBI), Talca 3480094, Chile"},{"name":"Instituto de Qu\u00edmica de Recursos Naturales, Universidad de Talca, Casilla 747, Talca 3480094, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00edctor","family":"Andrades","sequence":"additional","affiliation":[{"name":"Interdisciplinary Group on Mitochondrial Targeting and Bioenergetics (MIBI), Talca 3480094, Chile"},{"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 7810000, Chile"},{"name":"Network for Snake Venom Research and Drug Discovery, Santiago 7810000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristopher","family":"Almarza","sequence":"additional","affiliation":[{"name":"Interdisciplinary Group on Mitochondrial Targeting and Bioenergetics (MIBI), Talca 3480094, Chile"},{"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 7810000, Chile"},{"name":"Network for Snake Venom Research and Drug Discovery, Santiago 7810000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6099-0311","authenticated-orcid":false,"given":"Mar\u00eda Jes\u00fas","family":"Vera","sequence":"additional","affiliation":[{"name":"Interdisciplinary Group on Mitochondrial Targeting and Bioenergetics (MIBI), Talca 3480094, Chile"},{"name":"Laboratorio de Biolog\u00eda Celular, Instituto de Nutrici\u00f3n y Tecnolog\u00eda de los Alimento (INTA), Universidad de Chile, Santiago 7830490, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Interdisciplinary Group on Mitochondrial Targeting and Bioenergetics (MIBI), Talca 3480094, Chile"},{"name":"Laboratorio de Biolog\u00eda Celular, Instituto de Nutrici\u00f3n y Tecnolog\u00eda de los Alimento (INTA), Universidad de Chile, Santiago 7830490, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodrigo","family":"Pulgar","sequence":"additional","affiliation":[{"name":"Laboratorio de Gen\u00f3mica y Gen\u00e9tica de Interacciones Biol\u00f3gicas (LG2IB), Instituto de Nutrici\u00f3n y Tecnolog\u00eda de los Alimento (INTA), Universidad de Chile, El L\u00edbano 5524, Santiago 7830490, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1872-5133","authenticated-orcid":false,"given":"John","family":"Amalraj","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica de Recursos Naturales, Universidad de Talca, Casilla 747, Talca 3480094, 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":"Interdisciplinary Group on Mitochondrial Targeting and Bioenergetics (MIBI), Talca 3480094, Chile"},{"name":"Instituto de Qu\u00edmica de Recursos Naturales, Universidad de Talca, Casilla 747, Talca 3480094, Chile"},{"name":"Network for Snake Venom Research and Drug Discovery, Santiago 7810000, 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":"Interdisciplinary Group on Mitochondrial Targeting and Bioenergetics (MIBI), Talca 3480094, Chile"},{"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 7810000, Chile"},{"name":"Network for Snake Venom Research and Drug Discovery, Santiago 7810000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.trecan.2017.04.008","article-title":"Migrastatics-Anti-metastatic and Anti-invasion Drugs: Promises and Challenges","volume":"3","author":"Rosel","year":"2017","journal-title":"Trends Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Urra, F.A., Fuentes-Retamal, S., Palominos, C., Rodr\u00edguez-Lucart, Y.A., L\u00f3pez-Torres, C., and Araya-Maturana, R. (2021). Extracellular Matrix Signals as Drivers of Mitochondrial Bioenergetics and Metabolic Plasticity of Cancer Cells during Metastasis. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.751301"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1038\/ncb3039","article-title":"PGC-1\u03b1 mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis","volume":"16","author":"LeBleu","year":"2014","journal-title":"Nat. Cell Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1016\/j.celrep.2014.06.043","article-title":"A mitochondrial switch promotes tumor metastasis","volume":"8","author":"Porporato","year":"2014","journal-title":"Cell Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1186\/s13058-014-0434-6","article-title":"Mitochondrial dysfunction in some triple-negative breast cancer cell lines: Role of mTOR pathway and therapeutic potential","volume":"16","author":"Pelicano","year":"2014","journal-title":"Breast Cancer Res. BCR"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1172\/JCI64264","article-title":"Mitochondrial complex I activity and NAD+\/NADH balance regulate breast cancer progression","volume":"123","author":"Santidrian","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"C\u00f3rdova-Delgado, M., Fuentes-Retamal, S., Palominos, C., L\u00f3pez-Torres, C., Guzm\u00e1n-Rivera, D., Ram\u00edrez-Rodr\u00edguez, O., Araya-Maturana, R., and Urra, F.A. (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.","DOI":"10.3390\/antiox10101618"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Fuentes-Retamal, S., Sandoval-Acu\u00f1a, C., Peredo-Silva, L., Guzm\u00e1n-Rivera, D., Pavani, M., Torrealba, N., Truksa, J., Castro-Castillo, V., Catal\u00e1n, M., and Kemmerling, U. (2020). Complex Mitochondrial Dysfunction Induced by TPP+-Gentisic Acid and Mitochondrial Translation Inhibition by Doxycycline Evokes Synergistic Lethality in Breast Cancer Cells. Cells, 9.","DOI":"10.3390\/cells9020407"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"118","DOI":"10.3389\/fonc.2017.00118","article-title":"The Mitochondrial Complex(I)ty of Cancer","volume":"7","author":"Urra","year":"2017","journal-title":"Front. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1042\/BST20130088","article-title":"Molecular mechanism and physiological role of active\u2013deactive transition of mitochondrial complex I","volume":"41","author":"Babot","year":"2013","journal-title":"Biochem. Soc. Trans."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1089\/ars.2012.4698","article-title":"Conformational change of mitochondrial complex I increases ROS sensitivity during ischemia","volume":"19","author":"Gorenkova","year":"2013","journal-title":"Antioxid. Redox Signal."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"R\u00f6pke, M., Riepl, D., Saura, P., Di Luca, A., M\u00fchlbauer, M.E., Jussupow, A., Gamiz-Hernandez, A.P., and Kaila, V.R.I. (2021). Deactivation blocks proton pathways in the mitochondrial complex I. Proc. Natl. Acad. Sci. USA, 118.","DOI":"10.1073\/pnas.2019498118"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Chung, I., Grba, D.N., Wright, J.J., and Hirst, J. (2022). Making the leap from structure to mechanism: Are the open states of mammalian complex I identified by cryoEM resting states or catalytic intermediates?. Curr. Opin. Struct. Biol., 77.","DOI":"10.1016\/j.sbi.2022.102447"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2011","DOI":"10.1021\/bi501473h","article-title":"Selective Inhibition of Deactivated Mitochondrial Complex I by Biguanides","volume":"54","author":"Matsuzaki","year":"2015","journal-title":"Biochemistry"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/S0005-2728(96)00163-6","article-title":"Interaction of the mitochondrial NADH-ubiquinone reductase with rotenone as related to the enzyme active\/inactive transition","volume":"1319","author":"Grivennikova","year":"1997","journal-title":"Biochim. Biophys. Acta (BBA)-Bioenerg."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1042\/BJ20140620","article-title":"Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria","volume":"462","author":"Bridges","year":"2014","journal-title":"Biochem. J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.taap.2012.12.023","article-title":"An ortho-carbonyl substituted hydroquinone derivative is an anticancer agent that acts by inhibiting mitochondrial bioenergetics and by inducing G2\/M-phase arrest in mammary adenocarcinoma TA3","volume":"267","author":"Urra","year":"2013","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.taap.2015.12.005","article-title":"Small structural changes on a hydroquinone scaffold determine the complex I inhibition or uncoupling of tumoral oxidative phosphorylation","volume":"291","author":"Urra","year":"2016","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Urra, F.A., Mu\u00f1oz, F., C\u00f3rdova-Delgado, M., Ram\u00edrez, M.P., Pe\u00f1a-Ahumada, B., Rios, M., Cruz, P., Ahumada-Castro, U., Bustos, G., and Silva-Pavez, E. (2018). FR58P1a: A new uncoupler of OXPHOS that inhibits migration in triple-negative breast cancer cells via Sirt1\/AMPK\/\u03b21-integrin pathway. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-31367-9"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1039\/P19930001103","article-title":"Studies on quinones. Part 27. Diels\u2013Alder reaction of 8,8-dimethylnaphthalene-1,4,5(8H)-trione","volume":"10","author":"Valderrama","year":"1993","journal-title":"J. Chem. Soc. Perkin Trans. 1"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/S0040-4020(98)01083-7","article-title":"Regioselectivity in the Diels-Alder reaction of 8,8-dimethylnaphthalene-1,4,5(8H)-trione with 2,4-hexadien-1-ol","volume":"55","author":"Cassels","year":"1999","journal-title":"Tetrahedron"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1071\/CH13355","article-title":"On-Water Reactivity and Regioselectivity of Quinones in C\u2013N Coupling with Amines: Experimental and Theoretical Study","volume":"67","year":"2014","journal-title":"Aust. J. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.tetasy.2012.11.017","article-title":"Remote regio- and stereocontrol by the sulfinyl group: Diels\u2013Alder reaction of sulfinyl dienols and 8,8-dimethylnaphthalene-1,4,5(8H)-trione","volume":"24","author":"Almodovar","year":"2013","journal-title":"Tetrahedron Asymmetry"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Mart\u00ednez-Cifuentes, M., Salazar, R., Ram\u00edrez-Rodr\u00edguez, O., Weiss-L\u00f3pez, B., and Araya-Maturana, R. (2017). Experimental and Theoretical Reduction Potentials of Some Biologically Active ortho-Carbonyl para-Quinones. Molecules, 22.","DOI":"10.3390\/molecules22040577"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Donoso-Bustamante, V., Borrego, E.A., Schiaffino-Bustamante, Y., Guti\u00e9rrez, D.A., Millas-Vargas, J.P., Fuentes-Retamal, S., Correa, P., Carrillo, I., Aguilera, R.J., and Miranda, D. (2020). An acylhydroquinone derivative produces OXPHOS uncoupling and sensitization to BH3 mimetic ABT-199 (Venetoclax) in human promyelocytic leukemia cells. Bioorganic Chem., 100.","DOI":"10.1016\/j.bioorg.2020.103935"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"M\u00e9ndez, D., Donoso-Bustamante, V., Pablo Millas-Vargas, J., Pessoa-Mahana, H., Araya-Maturana, R., and Fuentes, E. (2021). Synthesis and pharmacological evaluation of acylhydroquinone derivatives as potent antiplatelet agents. Biochem. Pharmacol., 183.","DOI":"10.1016\/j.bcp.2020.114341"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4664","DOI":"10.1016\/j.bmc.2006.02.011","article-title":"Effects of 9,10-dihydroxy-4,4-dimethyl-5,8-dihydro-1(4H)-anthracenone derivatives on tumor cell respiration","volume":"14","author":"Cardona","year":"2006","journal-title":"Bioorganic Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Cassis, R., Scholz, M., Tapia, R., and Valderrama, J.A. (1987). Dienone-phenol rearrangement of naphthalenetriones. A route to 10-acetoxy5,6,7,8-tetra hydrophenanthrene-1,4-diones. J. Chem. Soc. Perkin Trans. 1, 2855\u20132859.","DOI":"10.1039\/p19870002855"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Vega, A., Ramirez-Rodr\u00edguez, O., Mart\u00ednez-Cifuentes, M., Iba\u00f1ez, A., and Araya-Maturana, R. (2009). 8,8-Diethyl-1,4,5,8-tetra-hydro-naphthalene-1,4,5-trione. Acta Crystallogr. Sect. E Struct. Rep. Online, 65.","DOI":"10.1107\/S1600536809001755"},{"key":"ref_30","first-page":"353","article-title":"Inhibitory effect of nordihydroguaiaretic acid and its tetra-acetylated derivative on respiration and growth of adenocarcinoma TA3 and its multiresistant variant TA3MTX-R","volume":"22","author":"Plaza","year":"2008","journal-title":"In Vivo"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.taap.2004.02.013","article-title":"Alterations of rat liver mitochondrial oxidative phosphorylation and calcium uptake by benzo[a]pyrene","volume":"198","author":"Salazar","year":"2004","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1042\/bj2180061","article-title":"Nutritional effects on mitochondrial bioenergetics. Alterations in oxidative phosphorylation by rat liver mitochondria","volume":"218","author":"Ferreira","year":"1984","journal-title":"Biochem. J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/0014-5793(93)80498-J","article-title":"Assay conditions for the mitochondrial NADH:coenzyme Q oxidoreductase","volume":"32","author":"Estornell","year":"1993","journal-title":"FEBS Lett."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/0005-2728(71)90089-2","article-title":"Quinone interaction with the respiratory chain-linked NADH dehydrogenase of beef heart mitochondria. II. Duroquinone reductase activity","volume":"226","author":"Ruzicka","year":"1971","journal-title":"Biochim. Biophys. Acta (BBA)-Bioenerg."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/0006-291X(70)90704-7","article-title":"Four quinone reduction sites in the NADH dehydrogenase complex","volume":"38","author":"Ruzicka","year":"1970","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"12005","DOI":"10.1021\/bi901706w","article-title":"Reactions of the flavin mononucleotide in complex I: A combined mechanism describes NADH oxidation coupled to the reduction of APAD+, ferricyanide, or molecular oxygen","volume":"48","author":"Birrell","year":"2009","journal-title":"Biochemistry"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1038\/sj.bjc.6605847","article-title":"NOX4-dependent ROS production by stromal mammary cells modulates epithelial MCF-7 cell migration","volume":"103","author":"Tobar","year":"2010","journal-title":"Br. J. Cancer"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/S0006-291X(02)00864-1","article-title":"Transforming growth factor-beta1 modulates matrix metalloproteinase-9 production through the Ras\/MAPK signaling pathway in transformed keratinocytes","volume":"296","author":"Guerrero","year":"2002","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Gueguen, N., Desquiret-Dumas, V., Leman, G., Chupin, S., Baron, S., Nivet-Antoine, V., Vessi\u00e8res, E., Ayer, A., Henrion, D., and Lenaers, G. (2015). Resveratrol Directly Binds to Mitochondrial Complex I and Increases Oxidative Stress in Brain Mitochondria of Aged Mice. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0144290"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1016\/j.bbabio.2008.11.003","article-title":"Differential effects of mitochondrial Complex I inhibitors on production of reactive oxygen species","volume":"1787","author":"Fato","year":"2009","journal-title":"Biochim. Biophys. Acta (BBA)-Bioenerg."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1152\/physrev.00006.2014","article-title":"Electronic Connection Between the Quinone and Cytochrome c Redox Pools and Its Role in Regulation of Mitochondrial Electron Transport and Redox Signaling","volume":"95","author":"Sarewicz","year":"2015","journal-title":"Physiol. Rev."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Kim, D.W., and Cho, J.-Y. (2018). NQO1 is Required for \u03b2-Lapachone-Mediated Downregulation of Breast-Cancer Stem-Cell Activity. Int. J. Mol. Sci., 19.","DOI":"10.20944\/preprints201810.0719.v1"},{"key":"ref_43","first-page":"4169","article-title":"Differential Suppression of Proliferation in MCF-7 and MDA-MB-231 Breast Cancer Cells Exposed to \u03b1-, \u03b3- and \u03b4-Tocotrienols Is Accompanied by Altered Expression of Oxidative Stress Modulatory Enzymes","volume":"30","author":"Hsieh","year":"2010","journal-title":"Anticancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/j.bbrc.2012.08.111","article-title":"NADPH quinone oxidoreductase 1 mediates breast cancer cell resistance to thymoquinone-induced apoptosis","volume":"426","author":"Sutton","year":"2012","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"6416","DOI":"10.1016\/S0021-9258(19)42173-X","article-title":"Properties and reaction mechanism of DT diaphorase from rat liver","volume":"249","author":"Hosoda","year":"1974","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Liu, F., Kalpage, H.A., Wang, D., Edwards, H., H\u00fcttemann, M., Ma, J., Su, Y., Carter, J., Li, X., and Polin, L. (2020). Cotargeting of Mitochondrial Complex I and Bcl-2 Shows Antileukemic Activity against Acute Myeloid Leukemia Cells Reliant on Oxidative Phosphorylation. Cancers, 12.","DOI":"10.3390\/cancers12092400"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1038\/s41416-020-01125-8","article-title":"Roles of mitochondria in the hallmarks of metastasis","volume":"124","author":"Scheid","year":"2021","journal-title":"Br. J. Cancer"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1080\/09168451.2020.1747974","article-title":"Exploring the binding pocket of quinone\/inhibitors in mitochondrial respiratory complex I by chemical biology approaches","volume":"84","author":"Murai","year":"2020","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1126\/science.ade3332","article-title":"Structural basis of mammalian respiratory complex I inhibition by medicinal biguanides","volume":"379","author":"Bridges","year":"2023","journal-title":"Science"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.canlet.2016.11.040","article-title":"AG311, a small molecule inhibitor of complex I and hypoxia-induced HIF-1\u03b1 stabilization","volume":"388","author":"Bastian","year":"2017","journal-title":"Cancer Lett."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Donati, G., Nicoli, P., Verrecchia, A., Vallelonga, V., Croci, O., Rodighiero, S., Audano, M., Cassina, L., Ghsein, A., and Binelli, G. (2023). Oxidative stress enhances the therapeutic action of a respiratory inhibitor in MYC-driven lymphoma. EMBO Mol. Med., 15.","DOI":"10.15252\/emmm.202216910"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Heinz, S., Freyberger, A., Lawrenz, B., Schladt, L., Schmuck, G., and Ellinger-Ziegelbauer, H. (2017). Mechanistic Investigations of the Mitochondrial Complex I Inhibitor Rotenone in the Context of Pharmacological and Safety Evaluation. Sci. Rep., 7.","DOI":"10.1038\/srep45465"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1111\/j.1432-1033.1994.00411.x","article-title":"Comparison of the inhibitory action of natural rotenone and its stereoisomers with various NADH-ubiquinone reductases","volume":"225","author":"Ueno","year":"1994","journal-title":"Eur. J. Biochem."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Zhou, Y., Zou, J., Xu, J., Zhou, Y., Cen, X., and Zhao, Y. (2023). Recent advances of mitochondrial complex I inhibitors for cancer therapy: Current status and future perspectives. Eur. J. Med. Chem., 251.","DOI":"10.1016\/j.ejmech.2023.115219"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.comptc.2013.03.007","article-title":"On the mechanism of biological activity of hydroquinone derivatives that inhibit tumor cell respiration. A theoretical study","volume":"1013","year":"2013","journal-title":"Comput. Theor. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Mart\u00ednez-Cifuentes, M., Monroy-C\u00e1rdenas, M., Millas-Vargas, J.P., Weiss-L\u00f3pez, B.E., and Araya-Maturana, R. (2019). Assessing Parameter Suitability for the Strength Evaluation of Intramolecular Resonance Assisted Hydrogen Bonding in o-Carbonyl Hydroquinones. Molecules, 24.","DOI":"10.3390\/molecules24020280"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"9354","DOI":"10.3390\/molecules19079354","article-title":"Intramolecular hydrogen bond in biologically active o-carbonyl hydroquinones","volume":"19","author":"Santos","year":"2014","journal-title":"Molecules"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"3057","DOI":"10.1016\/S0968-0896(02)00154-2","article-title":"Effects of 4,4-dimethyl-5,8-dihydroxynaphtalene-1-one and 4,4-dimethyl-5,8-dihydroxytetralone derivatives on tumor cell respiration","volume":"10","author":"Ferreira","year":"2002","journal-title":"Bioorganic Med. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"15903","DOI":"10.1021\/jacs.6b05797","article-title":"Quinone 1 e\u2212 and 2 e\u2212\/2 H+ Reduction Potentials: Identification and Analysis of Deviations from Systematic Scaling Relationships","volume":"138","author":"Huynh","year":"2016","journal-title":"J. Am. Chem. Soc."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1515\/hsz-2018-0164","article-title":"Five decades of research on mitochondrial NADH-quinone oxidoreductase (complex I)","volume":"399","author":"Ohnishi","year":"2018","journal-title":"Biol. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"4135","DOI":"10.1038\/s41467-020-17957-0","article-title":"Key role of quinone in the mechanism of respiratory complex I","volume":"11","author":"Kaszuba","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Ross, D., and Siegel, D. (2021). The diverse functionality of NQO1 and its roles in redox control. Redox Biol., 41.","DOI":"10.1016\/j.redox.2021.101950"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"3099","DOI":"10.1073\/pnas.052706799","article-title":"NQO1 stabilizes p53 through a distinct pathway","volume":"99","author":"Asher","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Kim, J., Kim, S.K., Kim, H.K., Mattson, M.P., and Hyun, D.H. (2013). Mitochondrial function in human neuroblastoma cells is up-regulated and protected by NQO1, a plasma membrane redox enzyme. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0069030"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Tsvetkov, P., Adler, J., Strobelt, R., Adamovich, Y., Asher, G., Reuven, N., and Shaul, Y. (2021). NQO1 Binds and Supports SIRT1 Function. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.671929"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/1756-9966-33-14","article-title":"Clinical implications of high NQO1 expression in breast cancers","volume":"33","author":"Yang","year":"2014","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Pradubyat, N., Sakunrangsit, N., Mutirangura, A., and Ketchart, W. (2020). NADPH: Quinone oxidoreductase 1 (NQO1) mediated anti-cancer effects of plumbagin in endocrine resistant MCF7 breast cancer cells. Phytomedicine, 66.","DOI":"10.1016\/j.phymed.2019.153133"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Glorieux, C., and Buc Calderon, P. (2019). Cancer Cell Sensitivity to Redox-Cycling Quinones is Influenced by NAD(P)H: Quinone Oxidoreductase 1 Polymorphism. Antioxidants, 8.","DOI":"10.3390\/antiox8090369"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Repas, J., Zupin, M., Vodlan, M., Verani\u010d, P., Gole, B., Poto\u010dnik, U., and Pavlin, M. (2022). Dual Effect of Combined Metformin and 2-Deoxy-D-Glucose Treatment on Mitochondrial Biogenesis and PD-L1 Expression in Triple-Negative Breast Cancer Cells. Cancers, 14.","DOI":"10.3390\/cancers14051343"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1186\/s40478-019-0712-8","article-title":"Inhibition of mitochondrial respiration prevents BRAF-mutant melanoma brain metastasis","volume":"7","author":"Prestegarden","year":"2019","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/B978-0-323-91095-8.00006-4","article-title":"Chapter 1\u2014Recent advances in molecular mechanisms of anticancer natural products that target mitochondrial bioenergetics","volume":"Volume 71","year":"2021","journal-title":"Studies in Natural Products Chemistry"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Alexandrova, A., and Lomakina, M. (2022). How does plasticity of migration help tumor cells to avoid treatment: Cytoskeletal regulators and potential markers. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.962652"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1006\/scbi.2000.0379","article-title":"Matrix metalloproteinases in tumor invasion and metastasis","volume":"10","author":"Stamenkovic","year":"2000","journal-title":"Semin. Cancer Biol."},{"key":"ref_74","first-page":"1355","article-title":"Expression of matrix metalloproteinases (MMPs) in primary human breast cancer: MMP-9 as a potential biomarker for cancer invasion and metastasis","volume":"34","author":"Merdad","year":"2014","journal-title":"Anticancer Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2570","DOI":"10.1002\/jcp.25349","article-title":"Mitochondria and Mitochondrial ROS in Cancer: Novel Targets for Anticancer Therapy","volume":"231","author":"Yang","year":"2016","journal-title":"J. Cell. Physiol."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Wang, R., Liang, L., Matsumoto, M., Iwata, K., Umemura, A., and He, F. (2023). Reactive Oxygen Species and NRF2 Signaling, Friends or Foes in Cancer?. Biomolecules, 13.","DOI":"10.3390\/biom13020353"}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/12\/8\/1597\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:30:56Z","timestamp":1760128256000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/12\/8\/1597"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,10]]},"references-count":76,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,8]]}},"alternative-id":["antiox12081597"],"URL":"https:\/\/doi.org\/10.3390\/antiox12081597","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,10]]}}}