Targeting of monocytes and macrophages by myxobacterial compounds as anti-cancer strategy

粘细菌化合物靶向单核细胞和巨噬细胞作为抗癌策略

• 批准号: 187865455
• 负责人: Professor Dr. Oliver Werz
• 金额: --
• 依托单位: Lehrstuhl für Pharmazeutische / Medizinische Chemie
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/187865455?language=en
• 关键词: Targeting; monocytes; macrophages; myxobacterial; compounds

Monocytes and macrophages (including M1 and M2 subtypes) constitute functional components of tumors, creating a tumor-promoting environment. Therefore, monocytes/macrophages are promising targets for chemotherapy, with the aim to repress inflammatory monocytes to hamper tumor initiation or macrophage infiltration, but also to enhance the M1 immuno-stimulating activity and to suppress M2 cells. Our preliminary work focused on the modulation of human monocytes and macrophage subsets by archazolid and pretubulysin, and revealed remarkable biological properties of these myxobacterial compounds enabling to intervene with inflammation-triggered cancer. We will now investigate how archazolid (I) targets eicosanoid release, (II) differentially modulates cytokine secretion in monocytes and macrophages, and (III) regulates monocyte-macrophage differentiation, macrophage activation, and induction of differentiation towards dendritic cells, involving vATPase. For pretubuylsin, the mode of action underlying the inhibition of TNFα release and the concomitant activation of Akt and ERK-1/2 signalling will be revealed. A lipidomic approach in monocytes/macrophages shall elucidate alterations in the lipid profile by soraphen A, an inhibitor of acetyl-coenzyme A carboxylase-1, and its value as tool compound in cancer research. Finally, various experimental settings of co-culturing with cancer cells may reveal how such pharmacological modulation of monocytes/macrophages by these compounds translates into anti-tumoral efficiency.

单核细胞和巨噬细胞(包括M1和M2亚型)构成了肿瘤的功能成分，创造了促进肿瘤的环境。因此，单核/巨噬细胞是很有希望的化疗靶点，其目的是抑制炎性单核细胞，以阻止肿瘤的起始或巨噬细胞的侵袭，同时也增强M1的免疫刺激活性，抑制M2细胞。我们的初步工作集中在古拉唑醇和管溶素前对人类单核细胞和巨噬细胞亚群的调节，并揭示了这些粘液细菌化合物的显著生物学特性，使其能够干预炎症引发的癌症。我们现在将研究古霉素类是如何针对二十烷类化合物的释放，(Ii)差异化地调节单核细胞和巨噬细胞的细胞因子的分泌，以及(Iii)调节单核巨噬细胞的分化，巨噬细胞的激活，以及涉及vATPase的树突状细胞的诱导分化。对于Pre-tubuylsin，抑制肿瘤坏死因子α释放以及伴随激活Akt和ERK-1/2信号的作用模式将被揭示。单核/巨噬细胞中的脂组学方法将阐明乙酰辅酶A羧基酶-1的抑制剂索拉芬A在脂谱中的变化及其作为工具化合物在癌症研究中的价值。最后，与癌细胞共培养的各种实验环境可能揭示这些化合物对单核/巨噬细胞的药理调节如何转化为抗肿瘤效率。