ZLDI-8 suppresses angiogenesis and vasculogenic mimicry in drug-resistant NSCLC in vitro and in vivo

The chemotherapy drugs for NSCLC often face the consequences of treatment failure due to acquired drug resistance. Tumor chemotherapy resistance is often accompanied by angiogenesis. Here, we aimed to investigate the effect and underlying mechanisms of ADAM-17 inhibitor ZLDI-8 we found before on angiogenesis and vasculogenic mimicry(VM) in drug-resistant NSCLC.The tube formation assay was used to evaluate angiogenesis and VM. Migration and invasion were assessed with transwell assays in the co-culture condition. To explore the underlying mechanisms of how ZLDI-8 inhibited tubes formation, ELISA assay and western blot assay were preformed. The effects of ZLDI-8 on angiogenesis in vivo were investigated in Matrigel plug, CAM and Rat aortic ring assays.In the present study, ZLDI-8 significantly inhibited the tube formation of human umbilical vein endothelial cells (HUVECs) in either normal medium or in tumor supernatants. Furthermore, ZLDI-8 also inhibited VM tubes formation of A549/Taxol cells. In the co-culture assay, the interaction between lung cancer cells and HUVECs promotes increased cell migration and invasion, while ZLDI-8 eliminates this promotion. Moreover, the VEGF secretion were decreased by ZLDI-8 and the expression of Notch1, Dll4, HIF1α and VEGF were inhibited by ZLDI-8. In addition, ZLDI-8 can inhibit blood vessel formation in the Matrigel plug, CAM and Rat aortic ring assays.ZLDI-8 inhibits angiogenesis and VM in drug-resistant NSCLC through suppressing Notch1-HIF1α-VEGF signaling pathway. This study lays the foundation for the discovery of drugs that inhibit angiogenesis and VM in drug resistant NSCLC.