Neural precursor cell expressed, developmentally downregulated 8-activating enzyme inhibitor MLN4924 sensitizes colorectal cancer cells to oxaliplatin by inducing DNA damage, G2 cell cycle arrest and apoptosis

摘要

Oxaliplatin-based chemotherapy is a primary treatment for patients with metastatic colorectal cancer (CRC); however, its efficacy is limited. Therefore, novel therapeutic agents are urgently required. MLN4924 is a first-in-class inhibitor of neural precursor cell expressed, developmentally downregulated 8 (NEDD8)-activating enzyme E1, and has entered various phase-I/II clinical trials for cancer therapy due to its significant anticancer efficacy. The aim of the present study was to examine the synergistic effect and underlying mechanisms of MLN4924 and oxaliplatin combined treatment for CRC. It was demonstrated that MLN4924 treatment induced the DNA damage response (DDR) by inactivating cullin-ring ubiquitin ligases, subsequently leading to cell cycle disturbance and apoptosis in CRC cells. MLN4924 treatment increased the oxaliplatin-induced DDR, G2 cell cycle arrest and apoptosis. Protein expression levels of phosphorylated checkpoint kinase 2 (p-CHK2), p21 and p53, which are well-known functional proteins involved in G2 cell cycle arrest, were assessed. p-CHK2 protein expression levels were increased following combined treatment with MLN4924 and oxaliplatin, whereas p21/p53 protein expression levels were not. In conclusion, MLN4924 treatment may sensitize CRC cells to oxaliplatin treatment by inducing the DDR and increasing protein expression levels of p-CHK2, leading to G2 cell cycle arrest and apoptosis. Therefore, combined MLN4924 and oxaliplatin-based chemotherapy may be a potential therapeutic strategy for the treatment of CRC.