4.7 Article

Triple Combination of Ascorbate, Menadione and the Inhibition of Peroxiredoxin-1 Produces Synergistic Cytotoxic Effects in Triple-Negative Breast Cancer Cells

Journal

ANTIOXIDANTS
Volume 9, Issue 4, Pages -

Publisher

MDPI
DOI: 10.3390/antiox9040320

Keywords

triple therapeutic combination; antioxidant enzyme; prooxidant agents; augmented prooxidant therapy; triple-negative breast cancer

Funding

  1. National Science Centre, Poland [2014/13/B/NZ5/01354]
  2. Irish Cancer Society Collaborative Cancer Research Centre BREAST-PREDICT [CCRC13GAL]
  3. Science Foundation Ireland Investigator Programme OPTi-PREDICT [15/IA/3104]
  4. Science Foundation Ireland Strategic Partnership Programme Precision Oncology Ireland POI [18/SPP/3522]
  5. Medical University of Warsaw [1M19/PM14/14]

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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.

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