Local anesthetic bupivacaine inhibits proliferation and metastasis of hepatocellular carcinoma cells via suppressing PI3K/Akt and MAPK signaling

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide.Retrospective studies suggest that using local/regional anesthetic (LA/RA) is associated with better outcomes in primary HCC patients. In this study, we evaluated the effects of LA/RA bupivacaine in HCC cells and the underlying molecular mechanisms. The biological functions of bupivacaine in HCC cells were evaluated by transcriptome RNA sequencing, cell viability assay, bromodeoxyuridine incorporation assay, colony formation assay, flow cytometry, western blot, wound healing assay, transwell cell migration assay, tumor xenograft formation, and lung metastasis assay. Bupivacaine suppressed proliferation and induced apoptosis of HepG2 and SNU-449 cells in a time-and dose-dependent manner. Bupivacaine treatment also decreased colony formation, migration, and invasion of HepG2 and SNU-449 cells. In mouse models, bupivacaine repressed tumor xenograft growth and lung metastasis of HepG2 cells. Transcriptome sequencing of HepG2 cells suggested that PI3K/Akt and MAPK signaling pathways were suppressed by bupivacaine treatment. In western blot analysis, bupivacaine reduced the expression of total and phosphorylated Akt, mTOR, and MAPK. Furthermore, reactivated PI3K/Akt and MAPK signaling by EGF or NRG1 partially reversed the effects of bupivacaine on cell growth, colony formation, and invasion of HCC cells. Local anesthetic bupivacaine suppressed proliferation, migration and invasion, and induced apoptosis of HCC cells. Our results provided novel insights into the local anesthetic bupivacaine in the therapy of HCC patients.

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

“…They also proved this might be the result of activation of ERK1/2 and p38, and then the activation increased cleaved caspase-3 and Bax levels and decreased BCL-2 level (10). The similar proapoptotic effect has been observed with bupivacaine as well (55). Another study validated ropivacaine's effect on caspase-3, and proposed that ropivacaine could damage the structure of mitochondria and interfere its function, then lead to cell death (56).…”

“…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).…”

“…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).…”

Bupivacaine modulates the apoptosis and ferroptosis in bladder cancer via phosphatidylinositol 3-kinase (PI3K)/AKT pathway

“…Bupivacaine, a common local anesthetic, could induced apoptosis and PI3K/PKB pathway inactivation [ 47 ]. Bupivacaine inhibits proliferation and metastasis of hepatocellular carcinoma cells via suppressing PI3K/Akt and MAPK signaling [ 53 ]. PI3K/AKT/mTOR signaling pathway promotes ferroptosis and oxidative stress through regulating SREBP1 mediated lipogenesis, and PI3K inhibitor could block the effect [ 49 ].…”

Dissection of action mechanisms of Zuogui Pill in the treatment of liver cancer based on machine learning and network pharmacology: A review

“…PI3K-Akt and MAPK pathways make a significant impact on regulating the cell cycle, proliferation, apoptosis, and metabolism. [25][26][27] On the other hand, key protein targets tended to have interactions among different key modules. For example, PTGS2, JUN, SELE were all involved in TNF signaling pathway.…”