Novel eIF4E/eIF4G protein-protein interaction inhibitors DDH-1 exhibits anti-cancer activity in vivo and in vitro.

Abstract (E)-2-(2-(2,3-dibromo-4,5-dimethoxybenzylidene)hydrazinyl)-4-(3,4-difluorophenyl) thiazole (DDH-1) is novel small molecule compound synthesized in our previous work. This study found that DDH-1 could inhibit the proliferation of various human lung cancer cells. Particularly, the IC50 for A549 cells was 8.59 μM. Interestingly, we found that DDH-1 inhibits eIF4E/eIF4G interaction. The flow cytometry (FACS) results have indicated that DDH-1 may induce G0/G1 cycle arrest by inhibiting the expression of Cyclin D1 and CDK4. DDH-1 may also cause apoptosis through the caspase-dependent pathway. Study of these mechanisms has shown that DDH-1 may prompt reactive oxygen species (ROS) generation, decrease the mitochondrial membrane potential (MMP), and stimulate DNA double-strand breaks (DSBs) in A549 cells. Study of the signal pathway has indicated that DDH-1 could activate JNK phosphorylation and inhibit ERK phosphorylation. Interestingly, NAC, which scavenges ROS, reversed the MMP decline, DNA damage, JNK phosphorylation activation, and ERK phosphorylation inhibition caused by DDH-1. Overall, these findings provide evidence that the eIF4E/eIF4G interaction inhibitors DDH-1 induces DNA damage and apoptosis in human lung cancer A549 cells.