Inhibition of vasculogenic mimicry by 22-benzyloxydaphlongaminone via glycolysis suppression.

Vasculogenic mimicry (VM) is a phenomenon in which tumor cells themselves form vascular-like tubular structures within the tumor. Identification of novel VM inhibitors is an important research subject in tumor biology. In this study, we focused on 22-benzyloxydaphlongaminone (22-BDO), a synthetic intermediate of isodaphlongamine H. We investigated its effects on VM formation and the underlying mechanism of action. We found that 22-BDO treatment suppressed VM formation in lung adenocarcinoma A549 cells. ChemProteoBase analysis revealed decreased expression of the glycolytic enzymes aldolase A and enolase 1 following 22-BDO treatment, with glycolysis-related proteins showing an overall downward trend. In contrast, no clear similarity to known compounds was observed, suggesting that 22-BDO has a novel mode of action. Furthermore, 22-BDO reduced intracellular ATP levels, and the inhibitory activity correlated with the antiproliferative activity observed for isodaphlongamine H and its synthetic intermediates. Cell death induced by 22-BDO was partially suppressed by the addition of sodium pyruvate. In addition, 2-deoxy-D-glucose also suppressed VM formation, suggesting that energy metabolic pathways, including glycolysis, are involved in VM formation. Taken together, these findings identify 22-BDO as a novel inhibitor of VM formation and suggest an association between metabolic alterations and VM suppression.