Ropivacaine enhanced the cisplatin-sensitivity of Human colorectal cancer cells by accelerating ROS-meditated apoptosis and ferroptosis

Abstract The failure of cisplatin treatment to human colorectal cancer due to cisplatin-sensitivity reduced, it’s necessary to find the new adjuvant agents to increase the cisplatin-sensitivity. Ropivacaine has been demonstrated to inhibit the proliferation and migration of variety of cancer cells, however, it remains unclear whether it could increase the cisplatin sensitivity of colorectal cancer cells. The cisplatin-resistant cell line for colorectal cancer named LOVO/DDP cells were established by repeated induction of different concentration of cisplatin, the cell viability, proliferation, migration, and apoptosis were assessed by Colony-forming assay, Transwell assay, Wound Healing and Annexin V/PI flow cytometry; JC-1 and ROS detection kits were used to determine the levels of mitochondrial membrane potential and reactive oxygen species (ROS). The expression of MMP-9, Nrf-2, GPX4, SLC7A11, SIRT1 proteins were detected by Western-blot and immunofluorescence. Compared with the control group, the activity of LOVO cells decreased significantly and that in LOVO/DDP cells decreased slightly with the increase of cisplatin. After the treatment of ropivacaine combined with cisplatin, the LOVO/DDP cells viability was significantly decreased than cisplatin alone ( P <0.01). Compared with cisplatin alone treatment group, the proliferation and migration of LOVO cells and LOVO/DDP cells were significantly reduced in combined group. Ropivacaine combined with cisplatin enhanced apoptosis, the production of ROS, induced mitochondrial dysfunction, and down-regulated anti-ferroptosis and SIRT1 proteins. Those above results demonstrated that ropivacaine could increase the chemosensitivity of cisplatin-resistant human colon cancer cells, and its mechanism may be through promoting cancer cell apoptosis and ferroptosis.