Bufalin enhances the anti-proliferative effect of sorafenib on human hepatocellular carcinoma cells through downregulation of ERK
ABSTRACT The purpose of this study was to investigate the effect of bufalin on the anti-proliferative activity of sorafenib in the human hepatocellular carcinoma (HCC) cell lines PLC/PRF/5 and Hep G-2 and to determine the relevant molecular mechanism. Concurrent treatment with sorafenib and bufalin at a fixed ratio (25:1) for 48 h resulted in synergistic growth inhibition in HCC cell lines as determined by CCK-8 cell viability assays. Exposure of both PLC/PRF/5 and Hep G-2 cells to this combination of sorafenib (6.25 μM) and bufalin (50 nM) resulted in noticeable increases in apoptotic cell death, as evidenced by the disruption of mitochondria, compared to treatment with either agent alone. Although both sorafenib (6.25 μM) and bufalin (250 nM) alone inhibited the phosphorylation of ERK, the reduction in pERK was more pronounced in the cells treated with a combination of bufalin (50 nM) and sorafenib (250 nM). Furthermore, the inhibitory effect of bufalin on pERK was blocked by the PI3kinase inhibitor LY294002, suggesting that the reduction in pERK induced by bufalin might be mediated by AKT in these two HCC cell lines. Taken together, the results of our study suggest that bufalin enhances the anti-cancer effects of sorafenib on PLC/PRF/5 and Hep G-2 by contributing to the downregulation of ERK.
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ABSTRACT: Cardiac glycosides (CGs) are compounds used for the treatment of cardiac failure which also display strong anti-cancer activity inducing impairment of cell proliferation or activation of cell death whether by apoptosis or autophagy. Despite the fact that the sodium/potassium (Na(+)/K(+))-ATPase is a well-known target of CGs, its involvement in the anti-cancer effect of these compounds remains to be validated. Importantly, related intracellular sensor(s)/transducer(s) needs further characterization. We will discuss here key mechanisms activated by CGs including their ability to modulate the cell cycle and to regulate the expression of anti-apoptotic Bcl-2 family members, two so far marginally investigated events.Mitochondrion 06/2012; 13(3). DOI:10.1016/j.mito.2012.06.003 · 3.52 Impact Factor
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ABSTRACT: Cardiac glycosides represent group of compounds isolated from plants and some animals. They have been using in the therapy of heart failure for many years. In spite of the fact that cytotoxic effect of many cardiac glycosides has been demonstrated. The mechanism of the cytotoxic action is very complicated and complex, where Na+/K+-ATPase plays crucial role. On the other hand, Na+/K+-ATPase is regulated by many endogenous factors including hormones or FXYD proteins, which role in the regulation of cell cycle is intensively studied. This review focuses the role of Na+/K+-ATPase in the regulation of cell growth, cell cycle and cell proliferation and involvement of cardiac glycosides in the regulation of Na+/K+-ATPase. Cytotoxic effect of cardiac glycosides is discussed in the connection with possible apoptotic mechanisms induced by these compounds. Novel strategies in cancer therapy based on the cardiac glycosides as well as possibilities in the overcoming multidrug resistance by cardiac glycosides are discussed too. The goal of this review is to present cardiac glycosides as not only pharmaceuticals used in heart failure, but also as potent cytotoxic agents with possible involvement in cancer treatment.Anti-cancer agents in medicinal chemistry 03/2013; DOI:10.2174/18715206113139990304 · 2.94 Impact Factor
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ABSTRACT: Liver cancer is the fifth most common cause of cancer death worldwide. The study of more effective anti-hepatoma drugs is urgently required. Bufalin has been isolated from a traditional Chinese medicine and possesses less toxicity to normal cells. However, it has been found to inhibit growth of cancer cells. In this study, we aimed to investigate the efficacy and mechanism of bufalin in Huh7, Hep3B and HA22T human hepatoma cells. The three cell lines were treated with bufalin, the proliferation was detected by WST-1 assay and cell cycle was detected by flow cytometry analysis. The results showed that bufalin inhibited the proliferation of hepatoma cells and regulated the hepatoma cell death program in a dose- and time-dependent manner without typical features of apoptosis. RT-PCR arrays were used to investigate the autophagy transcriptional response triggered by bufalin and 13 genes were altered and further confirmed by real-time PCR. The translation levels of selected genes were examined by western blot analysis to reveal the bufalin-induced autophagy cascade. Bufalin synergized with the JNK pathway to induce autophagy of hepatoma cells and is closely associated with the upregulation of TNF, BECN-1, MAPK and ATG8, together with the downregulation of Bcl-2 and Bid. Our study provided a multi-angle evaluation system for anti-hepatoma pharmacology for pre-clinical drug investigation. In this case, bufalin was capable of inducing hepatoma cell autophagy, suggesting a potential regimen for single or combined chemotherapy to overcome hepatoma in clinical practice.International Journal of Oncology 05/2013; 43(1). DOI:10.3892/ijo.2013.1942 · 3.03 Impact Factor