Demeclocycline Reduces the Growth of Human Brain Tumor-Initiating Cells: Direct Activity and Through Monocytes
Myeloid cells that infiltrate into brain tumors are deactivated or exploited by the tumor cells. We previously demonstrated that compromised microglia, monocytes, and macrophages in malignant gliomas could be reactivated by amphotericin-B to contain the growth of brain tumorinitiating cells (BTICs)....
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2020.00272/full |
| _version_ | 1818925999949086720 |
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| author | Susobhan Sarkar Susobhan Sarkar Yibo Li Yibo Li Reza Mirzaei Reza Mirzaei Khalil S. Rawji Khalil S. Rawji Candice C. Poon Candice C. Poon Jianxiong Wang Jianxiong Wang Mehul Kumar Mehul Kumar Pinaki Bose Pinaki Bose V. Wee Yong V. Wee Yong |
| author_facet | Susobhan Sarkar Susobhan Sarkar Yibo Li Yibo Li Reza Mirzaei Reza Mirzaei Khalil S. Rawji Khalil S. Rawji Candice C. Poon Candice C. Poon Jianxiong Wang Jianxiong Wang Mehul Kumar Mehul Kumar Pinaki Bose Pinaki Bose V. Wee Yong V. Wee Yong |
| author_sort | Susobhan Sarkar |
| collection | DOAJ |
| description | Myeloid cells that infiltrate into brain tumors are deactivated or exploited by the tumor cells. We previously demonstrated that compromised microglia, monocytes, and macrophages in malignant gliomas could be reactivated by amphotericin-B to contain the growth of brain tumorinitiating cells (BTICs). We identified meclocycline as another activator of microglia, so we sought to test whether its better-tolerated derivative, demeclocycline, also stimulates monocytes to restrict BTIC growth. Monocytes were selected for study as they would be exposed to demeclocycline in the circulation prior to entry into brain tumors to become macrophages. We found that demeclocycline increased the activity of monocytes in culture, as determined by tumor necrosis factor-α production and chemotactic capacity. The conditioned medium of demeclocycline-stimulated monocytes attenuated the growth of BTICs generated from human glioblastoma resections, as evaluated using neurosphere and alamarBlue assays, and cell counts. Demeclocycline also had direct effects in reducing BTIC growth. A global gene expression screen identified several genes, such as DNA damage inducible transcript 4, frizzled class receptor 5 and reactive oxygen species modulator 1, as potential regulators of demeclocycline-mediated BTIC growth reduction. Amongst several tetracycline derivatives, only demeclocycline directly reduced BTIC growth. In summary, we have identified demeclocycline as a novel inhibitor of the growth of BTICs, through direct effect and through indirect stimulation of monocytes. Demeclocycline is a candidate to reactivate compromised immune cells to improve the prognosis of patients with gliomas. |
| first_indexed | 2024-12-20T02:50:09Z |
| format | Article |
| id | doaj.art-ed69c87239664fc08c76aa7426a912dc |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-20T02:50:09Z |
| publishDate | 2020-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-ed69c87239664fc08c76aa7426a912dc2022-12-21T19:56:03ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-02-011110.3389/fimmu.2020.00272507915Demeclocycline Reduces the Growth of Human Brain Tumor-Initiating Cells: Direct Activity and Through MonocytesSusobhan Sarkar0Susobhan Sarkar1Yibo Li2Yibo Li3Reza Mirzaei4Reza Mirzaei5Khalil S. Rawji6Khalil S. Rawji7Candice C. Poon8Candice C. Poon9Jianxiong Wang10Jianxiong Wang11Mehul Kumar12Mehul Kumar13Pinaki Bose14Pinaki Bose15V. Wee Yong16V. Wee Yong17Department of Clinical Neurosciences, The Hotchkiss Brain Institute and the Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB, CanadaDepartment of Oncology, The Hotchkiss Brain Institute and the Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB, CanadaDepartment of Clinical Neurosciences, The Hotchkiss Brain Institute and the Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB, CanadaDepartment of Oncology, The Hotchkiss Brain Institute and the Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB, CanadaDepartment of Clinical Neurosciences, The Hotchkiss Brain Institute and the Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB, CanadaDepartment of Oncology, The Hotchkiss Brain Institute and the Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB, CanadaDepartment of Clinical Neurosciences, The Hotchkiss Brain Institute and the Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB, CanadaDepartment of Oncology, The Hotchkiss Brain Institute and the Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB, CanadaDepartment of Clinical Neurosciences, The Hotchkiss Brain Institute and the Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB, CanadaDepartment of Oncology, The Hotchkiss Brain Institute and the Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB, CanadaDepartment of Clinical Neurosciences, The Hotchkiss Brain Institute and the Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB, CanadaDepartment of Oncology, The Hotchkiss Brain Institute and the Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB, CanadaDepartment of Biochemistry and Molecular Biology, The Hotchkiss Brain Institute and the Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB, CanadaDepartment of Surgery, The Hotchkiss Brain Institute and the Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB, CanadaDepartment of Biochemistry and Molecular Biology, The Hotchkiss Brain Institute and the Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB, CanadaDepartment of Surgery, The Hotchkiss Brain Institute and the Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB, CanadaDepartment of Clinical Neurosciences, The Hotchkiss Brain Institute and the Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB, CanadaDepartment of Oncology, The Hotchkiss Brain Institute and the Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB, CanadaMyeloid cells that infiltrate into brain tumors are deactivated or exploited by the tumor cells. We previously demonstrated that compromised microglia, monocytes, and macrophages in malignant gliomas could be reactivated by amphotericin-B to contain the growth of brain tumorinitiating cells (BTICs). We identified meclocycline as another activator of microglia, so we sought to test whether its better-tolerated derivative, demeclocycline, also stimulates monocytes to restrict BTIC growth. Monocytes were selected for study as they would be exposed to demeclocycline in the circulation prior to entry into brain tumors to become macrophages. We found that demeclocycline increased the activity of monocytes in culture, as determined by tumor necrosis factor-α production and chemotactic capacity. The conditioned medium of demeclocycline-stimulated monocytes attenuated the growth of BTICs generated from human glioblastoma resections, as evaluated using neurosphere and alamarBlue assays, and cell counts. Demeclocycline also had direct effects in reducing BTIC growth. A global gene expression screen identified several genes, such as DNA damage inducible transcript 4, frizzled class receptor 5 and reactive oxygen species modulator 1, as potential regulators of demeclocycline-mediated BTIC growth reduction. Amongst several tetracycline derivatives, only demeclocycline directly reduced BTIC growth. In summary, we have identified demeclocycline as a novel inhibitor of the growth of BTICs, through direct effect and through indirect stimulation of monocytes. Demeclocycline is a candidate to reactivate compromised immune cells to improve the prognosis of patients with gliomas.https://www.frontiersin.org/article/10.3389/fimmu.2020.00272/fullgliomainnate immunitymonocytesmacrophagesmicrogliastem cells |
| spellingShingle | Susobhan Sarkar Susobhan Sarkar Yibo Li Yibo Li Reza Mirzaei Reza Mirzaei Khalil S. Rawji Khalil S. Rawji Candice C. Poon Candice C. Poon Jianxiong Wang Jianxiong Wang Mehul Kumar Mehul Kumar Pinaki Bose Pinaki Bose V. Wee Yong V. Wee Yong Demeclocycline Reduces the Growth of Human Brain Tumor-Initiating Cells: Direct Activity and Through Monocytes Frontiers in Immunology glioma innate immunity monocytes macrophages microglia stem cells |
| title | Demeclocycline Reduces the Growth of Human Brain Tumor-Initiating Cells: Direct Activity and Through Monocytes |
| title_full | Demeclocycline Reduces the Growth of Human Brain Tumor-Initiating Cells: Direct Activity and Through Monocytes |
| title_fullStr | Demeclocycline Reduces the Growth of Human Brain Tumor-Initiating Cells: Direct Activity and Through Monocytes |
| title_full_unstemmed | Demeclocycline Reduces the Growth of Human Brain Tumor-Initiating Cells: Direct Activity and Through Monocytes |
| title_short | Demeclocycline Reduces the Growth of Human Brain Tumor-Initiating Cells: Direct Activity and Through Monocytes |
| title_sort | demeclocycline reduces the growth of human brain tumor initiating cells direct activity and through monocytes |
| topic | glioma innate immunity monocytes macrophages microglia stem cells |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2020.00272/full |
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