PMID- 32053908
OWN - NLM
STAT- MEDLINE
DCOM- 20210226
LR  - 20211204
IS  - 2073-4409 (Electronic)
IS  - 2073-4409 (Linking)
VI  - 9
IP  - 2
DP  - 2020 Feb 11
TI  - Complex Mitochondrial Dysfunction Induced by TPP(+)-Gentisic Acid and 
      Mitochondrial Translation Inhibition by Doxycycline Evokes Synergistic Lethality 
      in Breast Cancer Cells.
LID - 10.3390/cells9020407 [doi]
LID - 407
AB  - 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(+)C(10)), 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(+)C(10) 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 alpha-ketoglutarate dehydrogenase complex (alphaKGDHC) 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 beta-methyl ester (mAsp) and dimethyl alpha-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 (pgc1alpha) 
      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(+)C(10) 
      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.
FAU - Fuentes-Retamal, Sebastian
AU  - Fuentes-Retamal S
AD  - Clinical and Molecular Pharmacology Program, Institute of Biomedical Sciences 
      (ICBM), Faculty of Medicine, University of Chile, Santiago 8380453, Chile.
FAU - Sandoval-Acuna, Cristian
AU  - Sandoval-Acuna C
AD  - Institute of Biotechnology, Czech Academy of Sciences, 25250 Prague, Czech 
      Republic.
FAU - Peredo-Silva, Liliana
AU  - Peredo-Silva L
AD  - School of Pharmacy, Faculty of Medicine, Andres Bello National University, 
      Santiago 8370149, Chile.
FAU - Guzman-Rivera, Daniela
AU  - Guzman-Rivera D
AD  - Clinical and Molecular Pharmacology Program, Institute of Biomedical Sciences 
      (ICBM), Faculty of Medicine, University of Chile, Santiago 8380453, Chile.
FAU - Pavani, Mario
AU  - Pavani M
AD  - Clinical and Molecular Pharmacology Program, Institute of Biomedical Sciences 
      (ICBM), Faculty of Medicine, University of Chile, Santiago 8380453, Chile.
FAU - Torrealba, Natalia
AU  - Torrealba N
AD  - Institute of Biotechnology, Czech Academy of Sciences, 25250 Prague, Czech 
      Republic.
FAU - Truksa, Jaroslav
AU  - Truksa J
AD  - Institute of Biotechnology, Czech Academy of Sciences, 25250 Prague, Czech 
      Republic.
FAU - Castro-Castillo, Vicente
AU  - Castro-Castillo V
AD  - Department of Organic and Physical Chemistry, Faculty of Chemical and 
      Pharmaceutical Sciences, University of Chile, Santiago 8380494, Chile.
FAU - Catalan, Mabel
AU  - Catalan M
AD  - Clinical and Molecular Pharmacology Program, Institute of Biomedical Sciences 
      (ICBM), Faculty of Medicine, University of Chile, Santiago 8380453, Chile.
FAU - Kemmerling, Ulrike
AU  - Kemmerling U
AD  - Developmental Biology, Program of Anatomy, Institute of Biomedical Sciences 
      (ICBM), Faculty of Medicine, University of Chile, Santiago 8380453, Chile.
FAU - Urra, Felix A
AU  - Urra FA
AD  - Clinical and Molecular Pharmacology Program, Institute of Biomedical Sciences 
      (ICBM), Faculty of Medicine, University of Chile, Santiago 8380453, Chile.
FAU - Ferreira, Jorge
AU  - Ferreira J
AD  - Clinical and Molecular Pharmacology Program, Institute of Biomedical Sciences 
      (ICBM), Faculty of Medicine, University of Chile, Santiago 8380453, Chile.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200211
PL  - Switzerland
TA  - Cells
JT  - Cells
JID - 101600052
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Gentisates)
RN  - 0 (Heterocyclic Compounds)
RN  - 0 (Organophosphorus Compounds)
RN  - 0 (tris(o-phenylenedioxy)cyclotriphosphazene)
RN  - EC 1.2.4.2 (Ketoglutarate Dehydrogenase Complex)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.11.3 (AMP-Activated Protein Kinase Kinases)
RN  - N12000U13O (Doxycycline)
RN  - VP36V95O3T (2,5-dihydroxybenzoic acid)
SB  - IM
MH  - AMP-Activated Protein Kinase Kinases
MH  - Antineoplastic Agents/*pharmacology
MH  - Apoptosis/drug effects
MH  - Breast Neoplasms/*drug therapy/genetics/pathology
MH  - Cell Proliferation/drug effects
MH  - Doxycycline/pharmacology
MH  - Drug Synergism
MH  - Female
MH  - Gentisates/chemistry/pharmacology
MH  - Heterocyclic Compounds/chemistry/pharmacology
MH  - Humans
MH  - Ketoglutarate Dehydrogenase Complex/antagonists & inhibitors/genetics
MH  - Mitochondria/*drug effects/pathology
MH  - Organophosphorus Compounds/chemistry/pharmacology
MH  - Oxidative Phosphorylation/drug effects
MH  - Protein Biosynthesis/*drug effects
MH  - Protein Kinases/genetics
MH  - Ribosomes/drug effects
PMC - PMC7072465
OTO - NOTNLM
OT  - decyl polyhydroxybenzoate triphenylphosphonium derivatives
OT  - doxycycline
OT  - inhibition of alpha-ketoglutarate dehydrogenase complex
OT  - inhibition of the electron transport chain
OT  - mitochondrial ribosome inhibition
OT  - mitochondrially targeted
COIS- The authors have no conflict of interest about this manuscript.
EDAT- 2020/02/15 06:00
MHDA- 2021/02/27 06:00
PMCR- 2020/02/01
CRDT- 2020/02/15 06:00
PHST- 2019/11/15 00:00 [received]
PHST- 2020/02/05 00:00 [revised]
PHST- 2020/02/07 00:00 [accepted]
PHST- 2020/02/15 06:00 [entrez]
PHST- 2020/02/15 06:00 [pubmed]
PHST- 2021/02/27 06:00 [medline]
PHST- 2020/02/01 00:00 [pmc-release]
AID - cells9020407 [pii]
AID - cells-09-00407 [pii]
AID - 10.3390/cells9020407 [doi]
PST - epublish
SO  - Cells. 2020 Feb 11;9(2):407. doi: 10.3390/cells9020407.