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

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.

Wang L ，Guo W ，Guan H ，Yan N ，Cai X ，Zhu L ... -  《-》

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

Zhang R ，Lian Y ，Xie K ，Cai Y ，Pan Y ，Zhu Y ... -  《-》

Erianin suppresses hepatocellular carcinoma cells through down-regulation of PI3K/AKT, p38 and ERK MAPK signaling pathways.

Hepatocellular carcinoma (HCC) is the dominant pathological type of primary liver cancer and no effective methods are available for its treatment. Erianin is a natural product extracted from Dendrobium, which possesses multiple pharmacological activities, including antioxidative and antitumor activity. To evaluate the anti-HCC activities of erianin and explore its underlying mechanism. MTT assay and Crystal Violet staining assay were used to select the non-toxic concentrations for the subsequent experiments. The colony formation assay and PCNA fluorescent staining were used to investigate the antiproliferative effects of erianin on human SMMC-7721 and HepG2 cells. Wound healing and transwell test were used to analyze cell migration and invasion. Caspase3 and Tunel staining were used to detect apoptosis. Western blot was used to examine the expression levels of proteins associated with invasion and key proteins in the phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), p38 and ERK mitogen-activated protein kinase (MAPK) signaling pathways. Erianin inhibited HCC cell proliferation in a dose-dependent manner. Decreased migration rate and invaded cells were observed with erianin supplement. The expression of invasion-associated proteins in the erianin group was also down-regulated. Besides, more apoptotic cells were observed after erianin treatment. For the molecular mechanism, erianin inhibited the phosphorylation of Akt, ERK and P38 in the PI3K/Akt and ERK/P38 pathway. We demonstrated, for the first time, that erianin inhibited the proliferation, migration, invasion and induced the apoptosis of HCC through PI3K/Akt, p38 and ERK MAPK signaling pathway, indicating that erianin is a promising agent for the HCC treatment.

Yang L ，Hu Y ，Zhou G ，Chen Q ，Song Z ... -  《-》

Columbamine suppresses hepatocellular carcinoma cells through down-regulation of PI3K/AKT, p38 and ERK1/2 MAPK signaling pathways.

Hepatocellular carcinoma (HCC) as primary liver cancer in adults is the most common cause led to internal cirrhosis responsible for patients' death, which resulted in nearly a million deaths worldwide on both males and females in the developing and developed countries. Unfortunately, up to date, there are no highly effective treatment of medicine on HCC as lack of comprehensive cellular and molecular mechanism. According to the sources of human ancient history of medicine, traditional medicine could provide unique treatment to discontinue the challenging HCC. In this study, we inspected the effect of Columbamine (Col; C20H21NO5), an alkaloid isolated from calumba, on HCC utilizing three HCC cell-lines i.e. SMMC7721, HepG2 and Hep3B. Our data collected from these cell-lines exhibit strong Col suppression on the cell growth accompanying the dosage-dependent suppression, and we further confirmed the suppression on the tumor-growth in animal model. Rational of the Col suppression presents cellular mechanism by limiting the proliferation and colony formation of the cells marked with decreased expression of PCNA. Meanwhile decreases of migration indicated with increasing expression of E-cadherin and decreasing expression of N-cadherin, and of invasion labelled with decreasing expressions of MMP2 and MMP9, are accompanying the Col suppression along with the Col promoted apoptosis of the tumor cells. This programmed cell death marketed with cleaved Caspase 3 plus PAPR proteins, up-regulation of BAD and down-regulation of BCL2 is linked the Col suppression to unique calcium-related pathways. Our results unveiled that the Columbamine suppression on HCC based on the traditional medicine are clearly associated with PI3K/AKT, p38 and ERK1/2 MAPKs signaling pathways and guide further research orientation for developing the Col medicine against hepatocellular carcinoma.

Lin Z ，Li S ，Guo P ，Wang L ，Zheng L ，Yan Z ，Chen X ，Cheng Z ，Yan H ，Zheng C ，Zhao C ... -  《-》

Ophiopogonin‑B targets PTP1B to inhibit the malignant progression of hepatocellular carcinoma by regulating the PI3K/AKT and AMPK signaling pathways.

Yuan F ，Gao Q ，Tang H ，Shi J ，Zhou Y ... -  《-》