Mitochondria dysfunction induced by decyl-TPP mitochondriotropic antioxidant based on caffeic acid AntiOxCIN 6 sensitizes cisplatin lung anticancer therapy due to a remodeling of energy metabolism.

Autor: Amorim R; CNC/UC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; CIBB - Center for Innovative Biomedicine and Biotecnhology, University of Coimbra, Coimbra, Portugal; CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal., Magalhães CC; CNC/UC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; CIBB - Center for Innovative Biomedicine and Biotecnhology, University of Coimbra, Coimbra, Portugal., Benfeito S; CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal., Cagide F; CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal., Tavares LC; CNC/UC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; CIBB - Center for Innovative Biomedicine and Biotecnhology, University of Coimbra, Coimbra, Portugal; CIVG - Vasco da Gama Research Center, University School Vasco da Gama - EUVG, Coimbra, Portugal., Santos K; CNC/UC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; CIBB - Center for Innovative Biomedicine and Biotecnhology, University of Coimbra, Coimbra, Portugal., Sardão VA; Multidisciplinary Institute of Ageing (MIA), University of Coimbra, Coimbra, Portugal., Datta S; Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, USA., Cortopassi GA; Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, USA., Baldeiras I; CNC/UC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; CIBB - Center for Innovative Biomedicine and Biotecnhology, University of Coimbra, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal., Jones JG; CNC/UC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; CIBB - Center for Innovative Biomedicine and Biotecnhology, University of Coimbra, Coimbra, Portugal., Borges F; CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal., Oliveira PJ; CNC/UC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; CIBB - Center for Innovative Biomedicine and Biotecnhology, University of Coimbra, Coimbra, Portugal., Teixeira J; CNC/UC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; CIBB - Center for Innovative Biomedicine and Biotecnhology, University of Coimbra, Coimbra, Portugal. Electronic address: jose.teixeira@uc.pt.
Jazyk: angličtina
Zdroj: Biochemical pharmacology [Biochem Pharmacol] 2024 Jan; Vol. 219, pp. 115953. Date of Electronic Publication: 2023 Nov 29.
DOI: 10.1016/j.bcp.2023.115953
Abstrakt: The pharmacological interest in mitochondria is very relevant since these crucial organelles are involved in the pathogenesis of multiple diseases, such as cancer. In order to modulate cellular redox/oxidative balance and enhance mitochondrial function, numerous polyphenolic derivatives targeting mitochondria have been developed. Still, due to the drug resistance emergence in several cancer therapies, significant efforts are being made to develop drugs that combine the induction of mitochondrial metabolic reprogramming with the ability to generate reactive oxygen species, taking into consideration the varying metabolic profiles of different cell types. We previously developed a mitochondria-targeted antioxidant (AntiOxCIN 6 ) by linking caffeic acid to lipophilic triphenylphosphonium cation through a 10-carbon aliphatic chain. The antioxidant activity of AntiOxCIN 6 has been documented but how the mitochondriotropic compound impact energy metabolism of both normal and cancer cells remains unknown. We demonstrated that AntiOxCIN 6 increased antioxidant defense system in HepG2 cells, although ROS clearance was ineffective. Consequently, AntiOxCIN 6 significantly decreased mitochondrial function and morphology, culminating in a decreased capacity in complex I-driven ATP production without affecting cell viability. These alterations were accompanied by an increase in glycolytic fluxes. Additionally, we demonstrate that AntiOxCIN 6 sensitized A549 adenocarcinoma cells for CIS-induced apoptotic cell death, while AntiOxCIN 6 appears to cause metabolic changes or a redox pre-conditioning on lung MRC-5 fibroblasts, conferring protection against cisplatin. We propose that length and hydrophobicity of the C10-TPP +  alkyl linker play a significant role in inducing mitochondrial and cellular toxicity, while the presence of the antioxidant caffeic acid appears to be responsible for activating cytoprotective pathways.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Paulo J. Oliveira and Fernanda Borges are cofounders of the CNC-UP spin-off company MitoTAG (Coimbra, Portugal). This SME had no involvement in the data collection, analysis and interpretation, writing of the manuscript, and in the decision to submit the manuscript for publication.
(Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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