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Research ArticleExperimental Studies

Docosahexaenoic Acid Potentiates the Anticancer Effect of the Menadione/Ascorbate Redox Couple by Increasing Mitochondrial Superoxide and Accelerating ATP Depletion

DONIKA IVANOVA, SEVERINA SEMKOVA, ZVEZDELINA YANEVA, BILIANA NIKOLOVA, ZHIVKO ZHELEV, RUMIANA BAKALOVA and ICHIO AOKI
Anticancer Research March 2023, 43 (3) 1213-1220; DOI: https://doi.org/10.21873/anticanres.16268
DONIKA IVANOVA
1Department of Pharmacology, Animal Physiology, Biochemistry and Chemistry, Faculty of Veterinary Medicine, Trakia University, Stara Zagora, Bulgaria;
2Department of Chemistry and Biochemistry, Faculty of Medicine, Trakia University, Stara Zagora, Bulgaria;
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SEVERINA SEMKOVA
3Department of Electroinduced and Adhesive Properties, Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Sofia, Bulgaria;
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ZVEZDELINA YANEVA
1Department of Pharmacology, Animal Physiology, Biochemistry and Chemistry, Faculty of Veterinary Medicine, Trakia University, Stara Zagora, Bulgaria;
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BILIANA NIKOLOVA
3Department of Electroinduced and Adhesive Properties, Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Sofia, Bulgaria;
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ZHIVKO ZHELEV
2Department of Chemistry and Biochemistry, Faculty of Medicine, Trakia University, Stara Zagora, Bulgaria;
3Department of Electroinduced and Adhesive Properties, Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Sofia, Bulgaria;
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RUMIANA BAKALOVA
4Department of Molecular Imaging and Theranostics, National Institutes for Quantum Science and Technology (QST), Chiba, Japan;
5Department of Physics, Biophysics and Radiology, Faculty of Medicine, Sofia University “St. Kliment Ohridski”, Sofia, Bulgaria
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  • For correspondence: bakalova.rumiana@qst.go.jp
ICHIO AOKI
4Department of Molecular Imaging and Theranostics, National Institutes for Quantum Science and Technology (QST), Chiba, Japan;
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Abstract

Background/Aim: Mitochondria-targeted anticancer drugs (“mitocans”) of natural origin are attractive candidates as adjuvants in cancer therapy. The redox couple menadione/ascorbate (M/A), which belongs to the “mitocans” family, induces selective oxidative stress in cancerous mitochondria and cells, respectively. DHA has also been found to regulate the mevalonate pathway, which is closely related to the prenylation of the cytotoxic menadione to the non-cytotoxic menaquinone. The aim of this study was to elucidate the ability of docosahexaenoic acid (DHA) to potentiate the anticancer effect of M/A by increasing ROS production, as well as affecting steady-state ATP levels in cancer cells. Materials and Methods: The experiments were performed on leukemic lymphocyte Jurkat. Cells were treated with DHA, M/A, and their combination (M/A/DHA) and four parameters were examined using the following assays: cell viability and proliferation, steady-state ATP, mitochondrial superoxide, intracellular hydroperoxides. Three independent experiments with two or six parallel measurements were performed for each parameter. Results: The triple combination M/A/DHA was characterized by much higher antiproliferative activity and cytotoxicity than M/A and DHA administered alone. DHA significantly accelerated M/A-induced ATP depletion in cells, which was accompanied by an additional increase in mitochondrial superoxide compared to cells treated with M/A or DHA alone. Conclusion: DHA significantly enhanced M/A-induced cytotoxicity in leukemic lymphocytes by inducing severe mitochondrial oxidative stress and accelerated ATP depletion. Selective DHA-mediated suppression of cholesterol synthesis in cancer cells (involved in the prenylation of cytotoxic menadione to the less cytotoxic phylloquinone), as well as DHA-mediated inhibition of superoxide dismutase are suggested to underlie the potentiation of the anticancer effect of M/A.

Key Words:
  • Docosahexaenoic acid
  • menadione/ascorbate
  • ATP
  • mitochondrial superoxide
  • leukemia
  • Received January 9, 2023.
  • Revision received January 26, 2023.
  • Accepted February 1, 2023.
  • Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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Anticancer Research: 43 (3)
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Docosahexaenoic Acid Potentiates the Anticancer Effect of the Menadione/Ascorbate Redox Couple by Increasing Mitochondrial Superoxide and Accelerating ATP Depletion
DONIKA IVANOVA, SEVERINA SEMKOVA, ZVEZDELINA YANEVA, BILIANA NIKOLOVA, ZHIVKO ZHELEV, RUMIANA BAKALOVA, ICHIO AOKI
Anticancer Research Mar 2023, 43 (3) 1213-1220; DOI: 10.21873/anticanres.16268

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Docosahexaenoic Acid Potentiates the Anticancer Effect of the Menadione/Ascorbate Redox Couple by Increasing Mitochondrial Superoxide and Accelerating ATP Depletion
DONIKA IVANOVA, SEVERINA SEMKOVA, ZVEZDELINA YANEVA, BILIANA NIKOLOVA, ZHIVKO ZHELEV, RUMIANA BAKALOVA, ICHIO AOKI
Anticancer Research Mar 2023, 43 (3) 1213-1220; DOI: 10.21873/anticanres.16268
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Keywords

  • Docosahexaenoic acid
  • menadione/ascorbate
  • ATP
  • mitochondrial superoxide
  • Leukemia
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