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

点击翻译按钮获取中文摘要

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.