Repurposed clindamycin suppresses pyroptosis in tumor-associated macrophages through Inhibition of caspase-1
Abstract Background The metastatic microenvironment is often rich in tumor-associated macrophages (TAMs). In uveal melanoma (UM), high levels of TAMs positively correlate with tumor progression and poorer prognosis. We hypothesize that the immunomodulation of TAMs can remodel the UM tumor microenvir...
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| Language: | English |
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BMC
2025-08-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Online Access: | https://doi.org/10.1186/s13046-025-03478-5 |
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| author | Adrian Weich Johannes Berges Cindy Flamann Katrin Bitterer Krishna Pal Singh David Chambers Christopher Lischer Xin Lai Olaf Wolkenhauer Carola Berking Gerhard Krönke Shailendra Gupta Heiko Bruns Julio Vera Research Group Macrophages |
| author_facet | Adrian Weich Johannes Berges Cindy Flamann Katrin Bitterer Krishna Pal Singh David Chambers Christopher Lischer Xin Lai Olaf Wolkenhauer Carola Berking Gerhard Krönke Shailendra Gupta Heiko Bruns Julio Vera Research Group Macrophages |
| author_sort | Adrian Weich |
| collection | DOAJ |
| description | Abstract Background The metastatic microenvironment is often rich in tumor-associated macrophages (TAMs). In uveal melanoma (UM), high levels of TAMs positively correlate with tumor progression and poorer prognosis. We hypothesize that the immunomodulation of TAMs can remodel the UM tumor microenvironment and make it more susceptible to therapeutic interventions. Methods In our work, we designed a novel computational pipeline that combines single-cell transcriptomics data, network analysis, multicriteria decision techniques, and pharmacophore-based docking simulations to select molecular targets and matching repurposable drugs for TAM immunomodulation. The method generates a ranking of drug-target interactions, the most promising of which are channeled towards experimental validation. Results To identify potential immunomodulatory targets, we created a network-based representation of the TAM interactome and extracted a regulatory core conditioned on UM expression data. Further, we selected 13 genes from this core (NLRP3, HMOX1, CASP1, GSTP1, NAMPT, HSP90AA1, B2M, ISG15, LTA4H, PTGS2, CXCL2, PLAUR, ZFP36, TANK) for pharmacophore-based virtual screening of FDA-approved compounds, followed by flexible molecular docking. Based on the ranked docking results, we chose the interaction between caspase-1 and clindamycin for experimental validation. Functional studies on macrophages confirmed that clindamycin inhibits caspase-1 activity and thereby inflammasome activation, leading to a decrease in IL-1β, IL-18, and gasdermin D cleavage products as well as a reduction in pyroptotic cell death. This clindamycin-mediated inhibition of caspase-1 was also observable in TAMs derived from the bone marrow of multiple myeloma patients. Conclusions Our computational workflow for drug repurposing identified clindamycin as an efficacious inhibitor of caspase-1 that suppresses inflammasome activity and pyroptosis in vitro in TAMs. |
| format | Article |
| id | doaj-art-b8a64a641f1047fda43879a6edf2ee79 |
| institution | Kabale University |
| issn | 1756-9966 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj-art-b8a64a641f1047fda43879a6edf2ee792025-08-20T03:43:37ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662025-08-0144111610.1186/s13046-025-03478-5Repurposed clindamycin suppresses pyroptosis in tumor-associated macrophages through Inhibition of caspase-1Adrian Weich0Johannes Berges1Cindy Flamann2Katrin Bitterer3Krishna Pal Singh4David Chambers5Christopher Lischer6Xin Lai7Olaf Wolkenhauer8Carola Berking9Gerhard Krönke10Shailendra Gupta11Heiko Bruns12Julio Vera13Research Group Macrophages14Department of Dermatology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Uniklinikum ErlangenDepartment of Internal Medicine 5, Hematology and Oncology, Friedrich- Alexander-Universität (FAU) Erlangen-Nürnberg and Uniklinikum ErlangenDepartment of Internal Medicine 5, Hematology and Oncology, Friedrich- Alexander-Universität (FAU) Erlangen-Nürnberg and Uniklinikum ErlangenDepartment of Internal Medicine 5, Hematology and Oncology, Friedrich- Alexander-Universität (FAU) Erlangen-Nürnberg and Uniklinikum ErlangenDepartment of Systems Biology and Bioinformatics, Universtität RostockDepartment of Internal Medicine 3, Uniklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-NürnbergDepartment of Internal Medicine 5, Hematology and Oncology, Friedrich- Alexander-Universität (FAU) Erlangen-Nürnberg and Uniklinikum ErlangenDepartment of Dermatology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Uniklinikum ErlangenDepartment of Systems Biology and Bioinformatics, Universtität RostockDepartment of Dermatology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Uniklinikum ErlangenDepartment of Internal Medicine 3, Uniklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-NürnbergDepartment of Systems Biology and Bioinformatics, Universtität RostockDepartment of Internal Medicine 5, Hematology and Oncology, Friedrich- Alexander-Universität (FAU) Erlangen-Nürnberg and Uniklinikum ErlangenDepartment of Dermatology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Uniklinikum ErlangenDepartment of Internal Medicine 5, Hematology and Oncology, Friedrich-Alexander Universität (FAU) Erlangen-NürnbergAbstract Background The metastatic microenvironment is often rich in tumor-associated macrophages (TAMs). In uveal melanoma (UM), high levels of TAMs positively correlate with tumor progression and poorer prognosis. We hypothesize that the immunomodulation of TAMs can remodel the UM tumor microenvironment and make it more susceptible to therapeutic interventions. Methods In our work, we designed a novel computational pipeline that combines single-cell transcriptomics data, network analysis, multicriteria decision techniques, and pharmacophore-based docking simulations to select molecular targets and matching repurposable drugs for TAM immunomodulation. The method generates a ranking of drug-target interactions, the most promising of which are channeled towards experimental validation. Results To identify potential immunomodulatory targets, we created a network-based representation of the TAM interactome and extracted a regulatory core conditioned on UM expression data. Further, we selected 13 genes from this core (NLRP3, HMOX1, CASP1, GSTP1, NAMPT, HSP90AA1, B2M, ISG15, LTA4H, PTGS2, CXCL2, PLAUR, ZFP36, TANK) for pharmacophore-based virtual screening of FDA-approved compounds, followed by flexible molecular docking. Based on the ranked docking results, we chose the interaction between caspase-1 and clindamycin for experimental validation. Functional studies on macrophages confirmed that clindamycin inhibits caspase-1 activity and thereby inflammasome activation, leading to a decrease in IL-1β, IL-18, and gasdermin D cleavage products as well as a reduction in pyroptotic cell death. This clindamycin-mediated inhibition of caspase-1 was also observable in TAMs derived from the bone marrow of multiple myeloma patients. Conclusions Our computational workflow for drug repurposing identified clindamycin as an efficacious inhibitor of caspase-1 that suppresses inflammasome activity and pyroptosis in vitro in TAMs.https://doi.org/10.1186/s13046-025-03478-5 |
| spellingShingle | Adrian Weich Johannes Berges Cindy Flamann Katrin Bitterer Krishna Pal Singh David Chambers Christopher Lischer Xin Lai Olaf Wolkenhauer Carola Berking Gerhard Krönke Shailendra Gupta Heiko Bruns Julio Vera Research Group Macrophages Repurposed clindamycin suppresses pyroptosis in tumor-associated macrophages through Inhibition of caspase-1 Journal of Experimental & Clinical Cancer Research |
| title | Repurposed clindamycin suppresses pyroptosis in tumor-associated macrophages through Inhibition of caspase-1 |
| title_full | Repurposed clindamycin suppresses pyroptosis in tumor-associated macrophages through Inhibition of caspase-1 |
| title_fullStr | Repurposed clindamycin suppresses pyroptosis in tumor-associated macrophages through Inhibition of caspase-1 |
| title_full_unstemmed | Repurposed clindamycin suppresses pyroptosis in tumor-associated macrophages through Inhibition of caspase-1 |
| title_short | Repurposed clindamycin suppresses pyroptosis in tumor-associated macrophages through Inhibition of caspase-1 |
| title_sort | repurposed clindamycin suppresses pyroptosis in tumor associated macrophages through inhibition of caspase 1 |
| url | https://doi.org/10.1186/s13046-025-03478-5 |
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