重用途克林霉素通过抑制caspase-1抑制肿瘤相关巨噬细胞的焦亡。

IF 12.8 1区 医学 Q1 ONCOLOGY
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
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引用次数: 0

摘要

背景:转移性微环境通常富含肿瘤相关巨噬细胞(tam)。在葡萄膜黑色素瘤(UM)中,高水平的tam与肿瘤进展和较差的预后呈正相关。我们假设tam的免疫调节可以重塑UM肿瘤微环境,使其更容易受到治疗干预。方法:在我们的工作中,我们设计了一个新的计算管道,将单细胞转录组学数据、网络分析、多标准决策技术和基于药物团的对接模拟相结合,以选择分子靶点和匹配可重复使用的TAM免疫调节药物。该方法生成药物-靶标相互作用的排序,其中最有希望的是进行实验验证。结果:为了确定潜在的免疫调节靶点,我们创建了基于网络的TAM相互作用组表示,并提取了以UM表达数据为条件的调控核心。此外,我们从该核心中选择了13个基因(NLRP3、HMOX1、CASP1、GSTP1、NAMPT、HSP90AA1、B2M、ISG15、LTA4H、PTGS2、CXCL2、PLAUR、ZFP36、TANK)进行基于药物团的虚拟筛选,并进行灵活的分子对接。根据排序对接结果,我们选择caspase-1与克林霉素的相互作用进行实验验证。巨噬细胞的功能研究证实,克林霉素抑制caspase-1活性,从而抑制炎性体的活化,导致IL-1β、IL-18和气皮蛋白D裂解产物的减少,并减少热噬细胞死亡。这种克林霉素介导的对caspase-1的抑制在多发性骨髓瘤患者骨髓的tam中也可以观察到。结论:我们的药物再利用计算工作流程确定了克林霉素是一种有效的caspase-1抑制剂,可以在体外抑制tam中的炎性体活性和焦亡。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Repurposed clindamycin suppresses pyroptosis in tumor-associated macrophages through Inhibition of caspase-1.

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.

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来源期刊
CiteScore
18.20
自引率
1.80%
发文量
333
审稿时长
1 months
期刊介绍: The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.
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