Atovaquone Suppresses Triple-Negative Breast Tumor Growth by Reducing Immune-Suppressive Cells
A major contributing factor in triple-negative breast cancer progression is its ability to evade immune surveillance. One mechanism for this immunosuppression is through ribosomal protein S19 (RPS19), which facilitates myeloid-derived suppressor cells (MDSCs) recruitment in tumors, which generate cy...
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MDPI AG
2021-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/10/5150 |
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| author | Nehal Gupta Shreyas Gaikwad Itishree Kaushik Stephen E. Wright Maciej M. Markiewski Sanjay K. Srivastava |
| author_facet | Nehal Gupta Shreyas Gaikwad Itishree Kaushik Stephen E. Wright Maciej M. Markiewski Sanjay K. Srivastava |
| author_sort | Nehal Gupta |
| collection | DOAJ |
| description | A major contributing factor in triple-negative breast cancer progression is its ability to evade immune surveillance. One mechanism for this immunosuppression is through ribosomal protein S19 (RPS19), which facilitates myeloid-derived suppressor cells (MDSCs) recruitment in tumors, which generate cytokines TGF-β and IL-10 and induce regulatory T cells (Tregs), all of which are immunosuppressive and enhance tumor progression. Hence, enhancing the immune system in breast tumors could be a strategy for anticancer therapeutics. The present study evaluated the immune response of atovaquone, an antiprotozoal drug, in three independent breast-tumor models. Our results demonstrated that oral administration of atovaquone reduced HCC1806, CI66 and 4T1 paclitaxel-resistant (4T1-PR) breast-tumor growth by 45%, 70% and 42%, respectively. MDSCs, TGF-β, IL-10 and Tregs of blood and tumors were analyzed from all of these in vivo models. Our results demonstrated that atovaquone treatment in mice bearing HCC1806 tumors reduced MDSCs from tumor and blood by 70% and 30%, respectively. We also observed a 25% reduction in tumor MDSCs in atovaquone-treated mice bearing CI66 and 4T1-PR tumors. In addition, a decrease in TGF-β and IL-10 in tumor lysates was observed in atovaquone-treated mice with a reduction in tumor Tregs. Moreover, a significant reduction in the expression of RPS19 was found in tumors treated with atovaquone. |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T11:27:36Z |
| publishDate | 2021-05-01 |
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| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-3ba2af4e1d5a4b52abb099f52a925b512023-11-21T19:29:11ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-05-012210515010.3390/ijms22105150Atovaquone Suppresses Triple-Negative Breast Tumor Growth by Reducing Immune-Suppressive CellsNehal Gupta0Shreyas Gaikwad1Itishree Kaushik2Stephen E. Wright3Maciej M. Markiewski4Sanjay K. Srivastava5Department of Biomedical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USADepartment of Immunotherapeutics and Biotechnology, Center for Tumor Immunology, and Targeted Cancer Therapy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USADepartment of Immunotherapeutics and Biotechnology, Center for Tumor Immunology, and Targeted Cancer Therapy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USADepartment of Biomedical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USADepartment of Immunotherapeutics and Biotechnology, Center for Tumor Immunology, and Targeted Cancer Therapy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USADepartment of Biomedical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USAA major contributing factor in triple-negative breast cancer progression is its ability to evade immune surveillance. One mechanism for this immunosuppression is through ribosomal protein S19 (RPS19), which facilitates myeloid-derived suppressor cells (MDSCs) recruitment in tumors, which generate cytokines TGF-β and IL-10 and induce regulatory T cells (Tregs), all of which are immunosuppressive and enhance tumor progression. Hence, enhancing the immune system in breast tumors could be a strategy for anticancer therapeutics. The present study evaluated the immune response of atovaquone, an antiprotozoal drug, in three independent breast-tumor models. Our results demonstrated that oral administration of atovaquone reduced HCC1806, CI66 and 4T1 paclitaxel-resistant (4T1-PR) breast-tumor growth by 45%, 70% and 42%, respectively. MDSCs, TGF-β, IL-10 and Tregs of blood and tumors were analyzed from all of these in vivo models. Our results demonstrated that atovaquone treatment in mice bearing HCC1806 tumors reduced MDSCs from tumor and blood by 70% and 30%, respectively. We also observed a 25% reduction in tumor MDSCs in atovaquone-treated mice bearing CI66 and 4T1-PR tumors. In addition, a decrease in TGF-β and IL-10 in tumor lysates was observed in atovaquone-treated mice with a reduction in tumor Tregs. Moreover, a significant reduction in the expression of RPS19 was found in tumors treated with atovaquone.https://www.mdpi.com/1422-0067/22/10/5150myeloid-derived tumor-suppressor cellsatovaquonerepurposingtriple-negative breast cancerregulatory T cellscytokines |
| spellingShingle | Nehal Gupta Shreyas Gaikwad Itishree Kaushik Stephen E. Wright Maciej M. Markiewski Sanjay K. Srivastava Atovaquone Suppresses Triple-Negative Breast Tumor Growth by Reducing Immune-Suppressive Cells International Journal of Molecular Sciences myeloid-derived tumor-suppressor cells atovaquone repurposing triple-negative breast cancer regulatory T cells cytokines |
| title | Atovaquone Suppresses Triple-Negative Breast Tumor Growth by Reducing Immune-Suppressive Cells |
| title_full | Atovaquone Suppresses Triple-Negative Breast Tumor Growth by Reducing Immune-Suppressive Cells |
| title_fullStr | Atovaquone Suppresses Triple-Negative Breast Tumor Growth by Reducing Immune-Suppressive Cells |
| title_full_unstemmed | Atovaquone Suppresses Triple-Negative Breast Tumor Growth by Reducing Immune-Suppressive Cells |
| title_short | Atovaquone Suppresses Triple-Negative Breast Tumor Growth by Reducing Immune-Suppressive Cells |
| title_sort | atovaquone suppresses triple negative breast tumor growth by reducing immune suppressive cells |
| topic | myeloid-derived tumor-suppressor cells atovaquone repurposing triple-negative breast cancer regulatory T cells cytokines |
| url | https://www.mdpi.com/1422-0067/22/10/5150 |
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