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Open AccessArticle

Complex Mitochondrial Dysfunction Induced by TPP+-Gentisic Acid and Mitochondrial Translation Inhibition by Doxycycline Evokes Synergistic Lethality in Breast Cancer Cells

1
Clinical and Molecular Pharmacology Program, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Santiago 8380453, Chile
2
Institute of Biotechnology, Czech Academy of Sciences, 25250 Prague, Czech Republic
3
School of Pharmacy, Faculty of Medicine, Andrés Bello National University, Santiago 8370149, Chile
4
Department of Organic and Physical Chemistry, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago 8380494, Chile
5
Developmental Biology, Program of Anatomy, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Santiago 8380453, Chile
*
Authors to whom correspondence should be addressed.
Cells 2020, 9(2), 407; https://doi.org/10.3390/cells9020407
Received: 15 November 2019 / Revised: 5 February 2020 / Accepted: 7 February 2020 / Published: 11 February 2020
(This article belongs to the Special Issue Mitochondria, Metabolism and Cancer)
The mitochondrion has emerged as a promising therapeutic target for novel cancer treatments because of its essential role in tumorigenesis and resistance to chemotherapy. Previously, we described a natural compound, 10-((2,5-dihydroxybenzoyl)oxy)decyl) triphenylphosphonium bromide (GA-TPP+C10), with a hydroquinone scaffold that selectively targets the mitochondria of breast cancer (BC) cells by binding to the triphenylphosphonium group as a chemical chaperone; however, the mechanism of action remains unclear. In this work, we showed that GA-TPP+C10 causes time-dependent complex inhibition of the mitochondrial bioenergetics of BC cells, characterized by (1) an initial phase of mitochondrial uptake with an uncoupling effect of oxidative phosphorylation, as previously reported, (2) inhibition of Complex I-dependent respiration, and (3) a late phase of mitochondrial accumulation with inhibition of α-ketoglutarate dehydrogenase complex (αKGDHC) activity. These events led to cell cycle arrest in the G1 phase and cell death at 24 and 48 h of exposure, and the cells were rescued by the addition of the cell-penetrating metabolic intermediates l-aspartic acid β-methyl ester (mAsp) and dimethyl α-ketoglutarate (dm-KG). In addition, this unexpected blocking of mitochondrial function triggered metabolic remodeling toward glycolysis, AMPK activation, increased expression of proliferator-activated receptor gamma coactivator 1-alpha (pgc1α) and electron transport chain (ETC) component-related genes encoded by mitochondrial DNA and downregulation of the uncoupling proteins ucp3 and ucp4, suggesting an AMPK-dependent prosurvival adaptive response in cancer cells. Consistent with this finding, we showed that inhibition of mitochondrial translation with doxycycline, a broad-spectrum antibiotic that inhibits the 28 S subunit of the mitochondrial ribosome, in the presence of GA-TPP+C10 significantly reduces the mt-CO1 and VDAC protein levels and the FCCP-stimulated maximal electron flux and promotes selective and synergistic cytotoxic effects on BC cells at 24 h of treatment. Based on our results, we propose that this combined strategy based on blockage of the adaptive response induced by mitochondrial bioenergetic inhibition may have therapeutic relevance in BC.
Keywords: inhibition of the electron transport chain; inhibition of alpha-ketoglutarate dehydrogenase complex; mitochondrially targeted; decyl polyhydroxybenzoate triphenylphosphonium derivatives; doxycycline; mitochondrial ribosome inhibition inhibition of the electron transport chain; inhibition of alpha-ketoglutarate dehydrogenase complex; mitochondrially targeted; decyl polyhydroxybenzoate triphenylphosphonium derivatives; doxycycline; mitochondrial ribosome inhibition
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Fuentes-Retamal, S.; Sandoval-Acuña, C.; Peredo-Silva, L.; Guzmán-Rivera, D.; Pavani, M.; Torrealba, N.; Truksa, J.; Castro-Castillo, V.; Catalán, M.; Kemmerling, U.; Urra, F.A.; Ferreira, J. Complex Mitochondrial Dysfunction Induced by TPP+-Gentisic Acid and Mitochondrial Translation Inhibition by Doxycycline Evokes Synergistic Lethality in Breast Cancer Cells. Cells 2020, 9, 407.

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