Ropivacaine suppresses tumor biological characteristics of human hepatocellular carcinoma via inhibiting IGF-1R/PI3K/AKT/mTOR signaling axis

Abstract

Ropivacaine, a common local anesthetic in the clinic, has anti-proliferative and pro-apoptotic effects in numerous cancers, however, the underlying regulatory mechanism of ropivacaine in hepatocellular carcinoma remains unclear. In the current study, human HepG2 cells were stimulated with different ropivacaine concentrations. Cell Counting Kit-8 assay, cell colony formation, and cell cycle were used to monitor cell viability. Cell apoptosis, migration, and invasion were determined by flow cytometry and transwell assays. Tumor xenograft experiments were performed to prove the anti-cancer effect of ropivacaine in vivo . A high dose of ropivacaine inhibited proliferation and promoted apoptosis of HepG2 cells in a dose-dependent manner. Ropivacaine challenge also arrested cells in the G2 phase, followed by a decline in the protein expression of cyclin D1 and cyclin-dependent kinase 2, and an increase in p27 levels in HepG2 cells. Additionally, different ropivacaine doses suppressed cell migration and invasion by upregulating E-cadherin expression and downregulating N-cadherin expression. Mechanically, ropivacaine challenge gradually restrained insulin-like growth factor-1 receptor (IGF-1 R) expression and the activities of phosphorylated-PI3K, AKT, and mTOR in HepG2 cells with increased ropivacaine doses. In the tumor xenograft experiment, ropivacaine was confirmed to inhibit tumor growth, accompanied by inhibition of the IGF-1 R/PI3K/AKT/mTOR signaling axis. In conclusion, ropivacaine suppressed tumor biological characteristics and promoted apoptosis, resulting in the suppression of hepatocellular carcinoma progression by targeting the IGF-1 R/PI3K/AKT/mTOR signaling pathway. It is possible that ropivacaine-mediated local anesthesia may be developed as a novel surgical adjuvant drug for treating hepatocellular carcinoma.

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

“…Ropivacaine has been showed to promote the apoptosis of numerous cancer cells including breast cancer, hepatocellular carcinoma cancer, and colon cancer [12][13][14][15]. Our ndings are consistent with above, ropivacaine combined with cisplatin signi cantly increase apoptosis in cisplatin-sensitive and cisplatin-resistant colon cancer cells when compared to cisplatin alone treatment.…”

Ropivacaine inhibits wound healing by suppressing the proliferation and migration of keratinocytes via the PI3K/AKT/mTOR Pathway

“…Wang et al [26] found that ropivacaine could interact with ITGB1 protein and inhibit the expression of ITGB1 protein in colon cancer cells, thereby affecting its downstream Akt and ERK signaling pathways. Also, at the molecular level, Zhang et al [42] have demonstrated that in the tumor xenograft experiment, ropivacaine was confirmed to inhibit tumor growth, accompanied by inhibition of the IGF-1 R/PI3K/AKT/mTOR signaling axis. Even at the transcriptional level, Zhang et al [15] confirmed that ropivacaine inhibited the proliferation, migration, invasion and increased apoptosis of GC cells by upregulating the expression of miR-520a-3p and further regulating the WEE1 and PI3K/AKT signaling pathways.…”

Long-term effect of anesthesia choice on patients with hepatocellular carcinoma undergoing open liver resection

“…Lidocaine down-regulated PI3K/Akt pathway via the reduction of ubiquitin specific peptidase 14 (USP14) level, leading to lower-level proliferation and invasion capacity (54). Similarly, ropivacaine and bupivacaine both could suppress PI3K/Akt pathway and reduce tumor cell proliferation and metastasis (55,57). Other pathways like MAPK can also be downregulated with LA treatment and involved in HCC progression (55).…”