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

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，创造了促肿瘤环境。因此，单核细胞/巨噬细胞是有希望的化疗靶点，其目的是抑制炎性单核细胞以阻碍肿瘤起始或巨噬细胞浸润，而且还增强M1免疫刺激活性并抑制M2细胞。我们的初步工作集中在通过archazolid和pretubulysin调节人单核细胞和巨噬细胞亚群，并揭示了这些粘细菌化合物能够干预炎症触发的癌症的显着生物学特性。我们现在将研究archazolid如何（I）靶向类花生酸释放，（II）差异调节单核细胞和巨噬细胞中的细胞因子分泌，（III）调节单核细胞-巨噬细胞分化，巨噬细胞活化和诱导树突状细胞分化，涉及vATP酶。对于pretubuylsin，将揭示抑制TNFα释放以及伴随的Akt和ERK-1/2信号传导激活的作用模式。单核细胞/巨噬细胞中的脂质组学方法将阐明乙酰辅酶A羧化酶-1抑制剂soraphen A的脂质谱改变及其作为癌症研究中的工具化合物的价值。最后，与癌细胞共培养的各种实验设置可以揭示这些化合物对单核细胞/巨噬细胞的这种药理学调节如何转化为抗肿瘤效率。

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.