Novel ADAM-17 inhibitor ZLDI-8 inhibits the proliferation and metastasis of chemo-resistant non-small-cell lung cancer by reversing Notch and epithelial mesenchymal transition in vitro and in vivo

Acquired drug-resistant non-small cell lung Cancer (NSCLC) has strong proliferation ability and is prone to epithelial-mesenchymal transition (EMT) and subsequent metastasis. Notch pathway mediates cell survival and EMT and is involved in the induction of multidrug resistance (MDR). ZLDI-8 is an inhibitor of Notch activating/cleaving Enzyme ADAM-17 we found before. However, the effects of ZLDI-8 on resistant NSCLC was unclear. Here, we demonstrated for the first time that ZLDI-8 could induce Apoptosis in lung Cancer, especially in chemotherapy-resistant non-small cell lung Cancer cells, and also inhibit migration, invasion and EMT phenotype of drug-resistant lung Cancer. ZLDI-8 inhibits the Notch signaling pathway, thereby regulating the expression of survival/Apoptosis and EMT-related proteins. Moreover, ZLDI-8 suppresses multidrug-resistant lung Cancer xenograft growth in vivo and blocks metastasis in a tail vein injection mice model. Therefore, ZLDI-8 is expected to be an effective agent in the treatment of drug-resistant lung Cancer.