Therapeutic cooperation between auranofin, a thioredoxin reductase inhibitor and anti-PD-L1 antibody for treatment of triple-negative breast cancer
| Autor: | Kathryn F. Tonissen, Debottam Sinha, Ashwini Makhale, Prahlad V. Raninga, Amanda L. Bain, Devathri Nanayakarra, Kum Kum Khanna, Murugan Kalimutho, Andy C Lee, Deepak Mittal, Yu-Yin Shih |
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| Rok vydání: | 2019 |
| Předmět: |
Cancer Research
Auranofin Thioredoxin-Disulfide Reductase medicine.medical_treatment Thioredoxin reductase Triple Negative Breast Neoplasms Antibodies B7-H1 Antigen Targeted therapy 03 medical and health sciences Mice 0302 clinical medicine Breast cancer PD-L1 Cell Line Tumor medicine Animals Humans Enzyme Inhibitors Triple-negative breast cancer Cell Proliferation Mice Inbred BALB C biology Cell Death business.industry medicine.disease Xenograft Model Antitumor Assays Immune checkpoint Oncology 030220 oncology & carcinogenesis Cancer research biology.protein Female Thioredoxin business Reactive Oxygen Species medicine.drug |
| Zdroj: | International journal of cancerReferences. 146(1) |
| ISSN: | 1097-0215 |
| Popis: | Triple-negative breast cancer (TNBCs) is a very aggressive and lethal form of breast cancer with no effective targeted therapy. Neoadjuvant chemotherapies and radiotherapy remains a mainstay of treatment with only 25-30% of TNBC patients responding. Thus, there is an unmet clinical need to develop novel therapeutic strategies for TNBCs. TNBC cells have increased intracellular oxidative stress and suppressed glutathione, a major antioxidant system, but still, are protected against higher oxidative stress. We screened a panel of antioxidant genes using the TCGA and METABRIC databases and found that expression of the thioredoxin pathway genes is significantly upregulated in TNBC patients compared to non-TNBC patients and is correlated with adverse survival outcomes. Treatment with auranofin (AF), an FDA-approved thioredoxin reductase inhibitor caused specific cell death and impaired the growth of TNBC cells grown as spheroids. Furthermore, AF treatment exerted a significant in vivo antitumor activity in multiple TNBC models including the syngeneic 4T1.2 model, MDA-MB-231 xenograft and patient-derived tumor xenograft by inhibiting thioredoxin redox activity. We, for the first time, showed that AF increased CD8+Ve T-cell tumor infiltration in vivo and upregulated immune checkpoint PD-L1 expression in an ERK1/2-MYC-dependent manner. Moreover, combination of AF with anti-PD-L1 antibody synergistically impaired the growth of 4T1.2 primary tumors. Our data provide a novel therapeutic strategy using AF in combination with anti-PD-L1 antibody that warrants further clinical investigation for TNBC patients. |
| Databáze: | OpenAIRE |
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