Title: 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
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.