Abstract
BackgroundAdvanced hepatocellular carcinoma (HCC) patients undergo significant tumor growth and metastasis. Here, we investigated bufalin for treating HCC, which exhibits anti-tumor activities in many tumor cell lines.MethodIn our experiment, HCCLM3-R cells were injected into nude mice to form subcutaneous human HCC tumors that were implanted into the liver to establish orthotopic transplantation tumor models. Bufalin was injected intraperitoneally at 1 or 1.5 mg/kg. LY294002 (100 mg/kg), a potent inhibitor of Akt which reduced the levels of pAkt in HCCLM3 cell lines, was injected intraperitoneally into one group thrice weekly. The control was injected with an equal volume of saline. Morphological alterations were evaluated in the liver and lung by stereomicroscopy, the apoptotic rate was measured by TUNEL staining, and expression of AKT/GSK3β/β-catenin/E-cadherin signaling pathway-related proteins was detected by immunohistochemistry (IHC) and western blot analysis.ResultsThese results suggested that the sizes and qualities of orthotopic transplanted tumors as well as pulmonary metastasis decreased markedly at the highest bufalin dose compared with that in the control. Orthotopic transplanted tumor tissues were necrotic in bufalin-treated groups and the apoptotic cell number was markedly higher at the highest bufalin dose compared with that in the control. Certain changes of expression of AKT/GSK3β/β-catenin/E-cadherin signaling pathway-related proteins were in tumor tissues, which were related to the bufalin dose. Similar results were observed in the LY294002-treated group.ConclusionBased on the above, one can draw conclusions that bufalin has significant anti-tumor activities and reduces the metastatic potential in an orthotopic transplantation tumor model of human HCC. Inhibition of AKT/GSK3β/β-catenin/E-cadherin signaling pathways by bufalin may show therapeutic effects in advanced HCC patients.
Highlights
Advanced hepatocellular carcinoma (HCC) patients undergo significant tumor growth and metastasis
Certain changes of expression of AKT/GSK3β/β-catenin/E-cadherin signaling pathway-related proteins were in tumor tissues, which were related to the bufalin dose
HCC cell line Stable red fluorescent protein-expressing HCCLM3 (HCCLM3-R) cells infected with a lentivirus containing full-length cDNA of red fluorescent protein were used in this study [13].The HCCLM3-R cells were maintained at 37°C with 5% CO2 in Dulbecco’s modified Eagle medium (DMEM) supplemented with 10% heat-inactivated fetal bovine serum (FBS)
Summary
Advanced hepatocellular carcinoma (HCC) patients undergo significant tumor growth and metastasis. Most HCC patients are diagnosed with advanced disease and generally have a poor prognosis with median survival is instrumental in angiogenesis and epithelial-tomesenchymal transition during tumorigenesis [7]. Nude mouse experiments have shown that suppression of the PI3K/AKT signaling pathway can inhibit tumor growth, reduce angiogenesis, and improve the tumor microenvironment [8]. Bufalin has been demonstrated to induce apoptosis in gastric cancer MGC803 cells and oral cancer CAL 27 cells by inhibition of the AKT signaling pathway [10,11]. Our previous in vitro studies have shown that the mechanisms underlying the antitumor effects of bufalin in hepatoma cells appear to be mediated by AKT/GSK3β/ β-catenin/E-cadherin signaling pathways [12]
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