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Triple Combination of Ascorbate, Menadione and the Inhibition of Peroxiredoxin-1 Produces Synergistic Cytotoxic Effects in Triple-Negative Breast Cancer Cells.
Antioxidants (Basel). 2020 Apr 16; 9(4)A

Abstract

Triple-negative breast cancer (TNBC) is an aggressive form of mammary malignancy currently without satisfactory systemic treatment options. Agents generating reactive oxygen species (ROS), such as ascorbate (Asc) and menadione (Men), especially applied in combination, have been proposed as an alternative anticancer modality. However, their effectiveness can be hampered by the cytoprotective effects of elevated antioxidant enzymes (e.g., peroxiredoxins, PRDX) in cancer. In this study, PRDX1 mRNA and protein expression were assessed in TNBC tissues by analysis of the online RNA-seq datasets and immunohistochemical staining of tissue microarray, respectively. We demonstrated that PRDX1 mRNA expression was markedly elevated in primary TNBC tumors as compared to non-malignant controls, with PRDX1 protein staining intensity correlating with favorable survival parameters. Subsequently, PRDX1 functionality in TNBC cell lines or non-malignant mammary cells was targeted by genetic silencing or chemically by auranofin (AUR). The PRDX1-knockdown or AUR treatment resulted in inhibition of the growth of TNBC cells in vitro. These cytotoxic effects were further synergistically potentiated by the incubation with a combination of the prooxidant agents, Asc and Men. In conclusion, we report that the PRDX1-related antioxidant system is essential for maintaining redox homeostasis in TNBC cells and can be an attractive therapeutic target in combination with ROS-generating agents.

Authors+Show Affiliations

Department of Clinical Immunology, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland.Department of Immunology, Medical University of Warsaw, Nielubowicza 5, 02-097 Warsaw, Poland.Department of Clinical Immunology, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland. Postgraduate School of Molecular Medicine, Medical University of Warsaw, Trojdena 2a, 02-091 Warsaw, Poland.International Centre for Cancer Vaccine Science, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, Poland.Cancer Biology and Therapeutics Laboratory, UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, D04 Dublin 4, Ireland.Cancer Biology and Therapeutics Laboratory, UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, D04 Dublin 4, Ireland.Cancer Biology and Therapeutics Laboratory, UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, D04 Dublin 4, Ireland.Department of Immunology, Medical University of Warsaw, Nielubowicza 5, 02-097 Warsaw, Poland.Department of Immunology, Medical University of Warsaw, Nielubowicza 5, 02-097 Warsaw, Poland.Department of Immunology, Medical University of Warsaw, Nielubowicza 5, 02-097 Warsaw, Poland.Cancer Biology and Therapeutics Laboratory, UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, D04 Dublin 4, Ireland. OncoMark Ltd., Nova UCD, D04 Dublin 4, Ireland.Department of Clinical Immunology, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland. Department of Immunology, Transplantology, and Internal Diseases, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32316111

Citation

Bajor, Malgorzata, et al. "Triple Combination of Ascorbate, Menadione and the Inhibition of Peroxiredoxin-1 Produces Synergistic Cytotoxic Effects in Triple-Negative Breast Cancer Cells." Antioxidants (Basel, Switzerland), vol. 9, no. 4, 2020.
Bajor M, Graczyk-Jarzynka A, Marhelava K, et al. Triple Combination of Ascorbate, Menadione and the Inhibition of Peroxiredoxin-1 Produces Synergistic Cytotoxic Effects in Triple-Negative Breast Cancer Cells. Antioxidants (Basel). 2020;9(4).
Bajor, M., Graczyk-Jarzynka, A., Marhelava, K., Kurkowiak, M., Rahman, A., Aura, C., Russell, N., Zych, A. O., Firczuk, M., Winiarska, M., Gallagher, W. M., & Zagozdzon, R. (2020). Triple Combination of Ascorbate, Menadione and the Inhibition of Peroxiredoxin-1 Produces Synergistic Cytotoxic Effects in Triple-Negative Breast Cancer Cells. Antioxidants (Basel, Switzerland), 9(4). https://doi.org/10.3390/antiox9040320
Bajor M, et al. Triple Combination of Ascorbate, Menadione and the Inhibition of Peroxiredoxin-1 Produces Synergistic Cytotoxic Effects in Triple-Negative Breast Cancer Cells. Antioxidants (Basel). 2020 Apr 16;9(4) PubMed PMID: 32316111.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Triple Combination of Ascorbate, Menadione and the Inhibition of Peroxiredoxin-1 Produces Synergistic Cytotoxic Effects in Triple-Negative Breast Cancer Cells. AU - Bajor,Malgorzata, AU - Graczyk-Jarzynka,Agnieszka, AU - Marhelava,Katsiaryna, AU - Kurkowiak,Malgorzata, AU - Rahman,Arman, AU - Aura,Claudia, AU - Russell,Niamh, AU - Zych,Agata O, AU - Firczuk,Malgorzata, AU - Winiarska,Magdalena, AU - Gallagher,William M, AU - Zagozdzon,Radoslaw, Y1 - 2020/04/16/ PY - 2020/02/28/received PY - 2020/04/10/revised PY - 2020/04/14/accepted PY - 2020/4/23/entrez PY - 2020/4/23/pubmed PY - 2020/4/23/medline KW - antioxidant enzyme KW - augmented prooxidant therapy KW - prooxidant agents KW - triple therapeutic combination KW - triple-negative breast cancer JF - Antioxidants (Basel, Switzerland) JO - Antioxidants (Basel) VL - 9 IS - 4 N2 - Triple-negative breast cancer (TNBC) is an aggressive form of mammary malignancy currently without satisfactory systemic treatment options. Agents generating reactive oxygen species (ROS), such as ascorbate (Asc) and menadione (Men), especially applied in combination, have been proposed as an alternative anticancer modality. However, their effectiveness can be hampered by the cytoprotective effects of elevated antioxidant enzymes (e.g., peroxiredoxins, PRDX) in cancer. In this study, PRDX1 mRNA and protein expression were assessed in TNBC tissues by analysis of the online RNA-seq datasets and immunohistochemical staining of tissue microarray, respectively. We demonstrated that PRDX1 mRNA expression was markedly elevated in primary TNBC tumors as compared to non-malignant controls, with PRDX1 protein staining intensity correlating with favorable survival parameters. Subsequently, PRDX1 functionality in TNBC cell lines or non-malignant mammary cells was targeted by genetic silencing or chemically by auranofin (AUR). The PRDX1-knockdown or AUR treatment resulted in inhibition of the growth of TNBC cells in vitro. These cytotoxic effects were further synergistically potentiated by the incubation with a combination of the prooxidant agents, Asc and Men. In conclusion, we report that the PRDX1-related antioxidant system is essential for maintaining redox homeostasis in TNBC cells and can be an attractive therapeutic target in combination with ROS-generating agents. SN - 2076-3921 UR - https://www.unboundmedicine.com/medline/citation/32316111/Triple_Combination_of_Ascorbate,_Menadione_and_the_Inhibition_of_Peroxiredoxin-1_Produces_Synergistic_Cytotoxic_Effects_in_Triple-Negative_Breast_Cancer_Cells L2 - https://www.mdpi.com/resolver?pii=antiox9040320 DB - PRIME DP - Unbound Medicine ER -
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