Triple Combination of Ascorbate, Menadione and the Inhibition of Peroxiredoxin-1 Produces Synergistic Cytotoxic Effects in Triple-Negative Breast Cancer Cells
Malgorzata Bajor,
Agnieszka Graczyk-Jarzynka,
Katsiaryna Marhelava,
Malgorzata Kurkowiak,
Arman Rahman,
Claudia Aura,
Niamh Russell,
Agata O. Zych,
Malgorzata Firczuk,
Magdalena Winiarska,
William M. Gallagher,
Radoslaw Zagozdzon
Affiliations
Malgorzata Bajor
Department of Clinical Immunology, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland
Agnieszka Graczyk-Jarzynka
Department of Immunology, Medical University of Warsaw, Nielubowicza 5, 02-097 Warsaw, Poland
Katsiaryna Marhelava
Department of Clinical Immunology, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland
Malgorzata Kurkowiak
International Centre for Cancer Vaccine Science, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, Poland
Arman Rahman
Cancer Biology and Therapeutics Laboratory, UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, D04 Dublin 4, Ireland
Claudia Aura
Cancer Biology and Therapeutics Laboratory, UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, D04 Dublin 4, Ireland
Niamh Russell
Cancer Biology and Therapeutics Laboratory, UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, D04 Dublin 4, Ireland
Agata O. Zych
Department of Immunology, Medical University of Warsaw, Nielubowicza 5, 02-097 Warsaw, Poland
Malgorzata Firczuk
Department of Immunology, Medical University of Warsaw, Nielubowicza 5, 02-097 Warsaw, Poland
Magdalena Winiarska
Department of Immunology, Medical University of Warsaw, Nielubowicza 5, 02-097 Warsaw, Poland
William M. Gallagher
Cancer Biology and Therapeutics Laboratory, UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, D04 Dublin 4, Ireland
Radoslaw Zagozdzon
Department of Clinical Immunology, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland
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.
