Bufalin attenuates the stage and metastatic potential of hepatocellular carcinoma in nude mice

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.

Bufalin reverses intrinsic and acquired drug resistance to cisplatin through the AKT signaling pathway in gastric cancer cells

“…Our previous study demonstrated that bufalin markedly inhibits proliferation and promotes apoptosis through endoplasmic reticulum stress in hepatocellular carcinoma cells (21). Experimental studies have shown that bufalin affects cancer cells by inhibiting the AKT pathway (22)(23)(24)(25). The present study demonstrated that intrinsic and acquired resistance to cisplatin can be diminished by bufalin, which affects the AKT pathway in GC cells.…”

“…The present study demonstrated that activation of the AKT pathway contributes to intrinsic and acquired resistance to cisplatin, and blocking the AKT pathway with bufalin enhances the efficacy of cisplatin in GC cells. (20), has been tested in clinical trials to treat advanced hepatocellular carcinoma, non-small-cell lung cancer and pancreatic cancer (28); and has been shown experimentally to inhibit cancer through the AKT pathway (22)(23)(24)(25). In the present study, bufalin inhibited the activation of AKT and its downstream molecules GSK-3β, mTOR, S6K and 4EBP1; and when combined with cisplatin, inhibited proliferation and promoted apoptosis of GC cells by diminishing activation of the AKT y under normoxic and hypoxic conditions.…”

Chemical constituents and antimicrobial properties of <i>Phyllanthus amarus</i> (Schum & Thonn)

“…It is a component found in many Chinese traditional medicine. Bufalin has an antitumor effect against various malignancies such as hepatocellular and lung carcinoma (Zhang, 2014;Wu, 2014;Qiu et al, 2013).…”

Radiosynthesis and pharmacokinetics of [¹⁸F]fluoroethyl bufalin in hepatocellular carcinoma-bearing mice

“…Preceding findings have revealed that the anticancer activity of bufalin could be attributed to its prevention of cell proliferation, instruction of apoptosis, disturbance of the cell cycle, and modulation of the immune response 7–9. Earlier study of ours revealed that bufalin had convincing anticancer growth and reduced the metastatic potentials in the human hepatocellular carcinoma-transplanted tumor model, and the fundamental mechanism was in part mediated by the signaling pathway of the Akt–GSK3β–β-catenin–E-cadherin 10,11. These results indicated that bufalin might be a purposeful constituent for cancer treatment.…”