Novel Methods of Targeting IL-1 Signalling for the Treatment of Breast Cancer Bone Metastasis
Breast cancer bone metastasis is currently incurable. Evidence suggests that inhibiting IL-1 signalling with the IL1R antagonist, Anakinra, or the IL1β antibody, Canakinumab, prevents metastasis and almost eliminates breast cancer growth in the bone. However, these drugs increase primary tumour grow...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-10-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/19/4816 |
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| author | Jiabao Zhou Jennifer M. Down Christopher N. George Jessica Murphy Diane V. Lefley Claudia Tulotta Marwa A. Alsharif Michael Leach Penelope D. Ottewell |
| author_facet | Jiabao Zhou Jennifer M. Down Christopher N. George Jessica Murphy Diane V. Lefley Claudia Tulotta Marwa A. Alsharif Michael Leach Penelope D. Ottewell |
| author_sort | Jiabao Zhou |
| collection | DOAJ |
| description | Breast cancer bone metastasis is currently incurable. Evidence suggests that inhibiting IL-1 signalling with the IL1R antagonist, Anakinra, or the IL1β antibody, Canakinumab, prevents metastasis and almost eliminates breast cancer growth in the bone. However, these drugs increase primary tumour growth. We, therefore, investigated whether targeting other members of the IL-1 pathway (Caspase-1, IL1β or IRAK1) could reduce bone metastases without increasing tumour growth outside of the bone. Inhibition of IL-1 via MLX01 (IL1β secretion inhibitor), VRT043198/VX765 (Caspase-1 inhibitor), Pacritinib (IRAK1 inhibitor) or Anakinra (IL1R antagonist) on tumour cell viability, migration and invasion were assessed in mouse mammary E0771 and Py8119 cells in vitro and on primary tumour growth, spontaneous metastasis and metastatic outgrowth in vivo. In vitro, Inhibition of IL-1 signalling by MLX01, VRT043198 and Anakinra reduced migration of E0771 and Py8119 cells and reversed tumour-derived IL1β induced-increased invasion and migration towards bone cells. In vivo, VX765 and Anakinra significantly reduced spontaneous metastasis and metastatic outgrowth in the bone, whereas MLX01 reduced primary tumour growth and bone metastasis. Pacritinib had no effect on metastasis in vitro or in vivo. Targeting IL-1 signalling with small molecule inhibitors may provide a new therapeutic strategy for breast cancer bone metastasis. |
| first_indexed | 2024-03-09T21:56:52Z |
| format | Article |
| id | doaj.art-8556ed06c1ec4965bc4191ab08731a65 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T21:56:52Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-8556ed06c1ec4965bc4191ab08731a652023-11-23T19:57:03ZengMDPI AGCancers2072-66942022-10-011419481610.3390/cancers14194816Novel Methods of Targeting IL-1 Signalling for the Treatment of Breast Cancer Bone MetastasisJiabao Zhou0Jennifer M. Down1Christopher N. George2Jessica Murphy3Diane V. Lefley4Claudia Tulotta5Marwa A. Alsharif6Michael Leach7Penelope D. Ottewell8Academic Unit of Clinical Oncology, Department of Oncology and Metabolism, Medical School, University of Sheffield, Sheffield S10 2RX, UKAcademic Unit of Clinical Oncology, Department of Oncology and Metabolism, Medical School, University of Sheffield, Sheffield S10 2RX, UKAcademic Unit of Clinical Oncology, Department of Oncology and Metabolism, Medical School, University of Sheffield, Sheffield S10 2RX, UKAcademic Unit of Clinical Oncology, Department of Oncology and Metabolism, Medical School, University of Sheffield, Sheffield S10 2RX, UKAcademic Unit of Clinical Oncology, Department of Oncology and Metabolism, Medical School, University of Sheffield, Sheffield S10 2RX, UKAcademic Unit of Clinical Oncology, Department of Oncology and Metabolism, Medical School, University of Sheffield, Sheffield S10 2RX, UKAcademic Unit of Clinical Oncology, Department of Oncology and Metabolism, Medical School, University of Sheffield, Sheffield S10 2RX, UKSchool of Science, University of Greenwich at Medway, Chatham ME4 4TB, UKAcademic Unit of Clinical Oncology, Department of Oncology and Metabolism, Medical School, University of Sheffield, Sheffield S10 2RX, UKBreast cancer bone metastasis is currently incurable. Evidence suggests that inhibiting IL-1 signalling with the IL1R antagonist, Anakinra, or the IL1β antibody, Canakinumab, prevents metastasis and almost eliminates breast cancer growth in the bone. However, these drugs increase primary tumour growth. We, therefore, investigated whether targeting other members of the IL-1 pathway (Caspase-1, IL1β or IRAK1) could reduce bone metastases without increasing tumour growth outside of the bone. Inhibition of IL-1 via MLX01 (IL1β secretion inhibitor), VRT043198/VX765 (Caspase-1 inhibitor), Pacritinib (IRAK1 inhibitor) or Anakinra (IL1R antagonist) on tumour cell viability, migration and invasion were assessed in mouse mammary E0771 and Py8119 cells in vitro and on primary tumour growth, spontaneous metastasis and metastatic outgrowth in vivo. In vitro, Inhibition of IL-1 signalling by MLX01, VRT043198 and Anakinra reduced migration of E0771 and Py8119 cells and reversed tumour-derived IL1β induced-increased invasion and migration towards bone cells. In vivo, VX765 and Anakinra significantly reduced spontaneous metastasis and metastatic outgrowth in the bone, whereas MLX01 reduced primary tumour growth and bone metastasis. Pacritinib had no effect on metastasis in vitro or in vivo. Targeting IL-1 signalling with small molecule inhibitors may provide a new therapeutic strategy for breast cancer bone metastasis.https://www.mdpi.com/2072-6694/14/19/4816breast cancerbone metastasisIL1βmouse models |
| spellingShingle | Jiabao Zhou Jennifer M. Down Christopher N. George Jessica Murphy Diane V. Lefley Claudia Tulotta Marwa A. Alsharif Michael Leach Penelope D. Ottewell Novel Methods of Targeting IL-1 Signalling for the Treatment of Breast Cancer Bone Metastasis Cancers breast cancer bone metastasis IL1β mouse models |
| title | Novel Methods of Targeting IL-1 Signalling for the Treatment of Breast Cancer Bone Metastasis |
| title_full | Novel Methods of Targeting IL-1 Signalling for the Treatment of Breast Cancer Bone Metastasis |
| title_fullStr | Novel Methods of Targeting IL-1 Signalling for the Treatment of Breast Cancer Bone Metastasis |
| title_full_unstemmed | Novel Methods of Targeting IL-1 Signalling for the Treatment of Breast Cancer Bone Metastasis |
| title_short | Novel Methods of Targeting IL-1 Signalling for the Treatment of Breast Cancer Bone Metastasis |
| title_sort | novel methods of targeting il 1 signalling for the treatment of breast cancer bone metastasis |
| topic | breast cancer bone metastasis IL1β mouse models |
| url | https://www.mdpi.com/2072-6694/14/19/4816 |
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