Venenum Bufonis, a traditional Chinese medicine, is widely used in the treatment of liver cancer in modern Chinese medical practices. In our search for anti-hepatoma constituents in Venenum Bufonis, bufotalin, bufalin, telocinobufagin and cinobufagin were obtained. Bufotalin was the most potent active compound among these four bufadienolides, and it exerted stronger inhibitory effect on the viability of doxorubicin-induced multidrug resistant liver cancer cells (R-HepG2) than that of their parent cells HepG2. Structure-activity relationship analysis indicated that the acetyl group linked to C-16 of bufadienolides might be useful for increasing anti-hepatoma activity. Further mechanistic studies revealed that bufotalin treatment induced cell cycle arrest at G(2)/M phase through down-regulation of Aurora A, CDC25, CDK1, cyclin A and cyclin B1, as well as up-regulation of p53 and p21. Bufotalin treatment also induced apoptosis which was accompanied by decrease in mitochondrial membrane potential, increases in intracellular calcium level and reactive oxygen species production, activations of caspase-9 and -3, cleavage of poly ADP-ribose polymerase (PARP) as well as changes in the expressions of bcl-2 and bax. It was also found that the inhibition of Akt expression and phosphorylation was involved in apoptosis induction, and specific Akt inhibitor LY294002 or siRNA targeting Akt can synergistically enhanced bufotalin-induced apoptosis. In vivo study showed that bufotalin significantly inhibited the growth of xenografted R-HepG2 cells, without body weight loss or marked toxicity towards the spleen. These results indicate that bufotalin has a promising potential to become a novel anti-cancer agent for the treatment of liver cancer with multidrug resistance.
"As shown in Fig. 5A and 5B, The percentage of apoptotic MCF-7 cells including early and late apoptotic cells was increased from 33.59% to 67.43% in a dose-dependent manner after treatment with compound 7 for 48 h, indicating that compound 7 could induce apoptosis . It was further supported by the fact that compound 7 triggered the cleavage of PARP (Fig. 5C), a hallmark of apoptosis . Mitochondrial apoptosis pathway, also known as intrinsic apoptotic pathway, is accompanied by the decrease of mitochondrial membrane potential, the translocation of cytochrome c from the mitochondria to the cytosol and the activation of downstream caspases . "
"Bufotalin. Zhang et al.  observed that four bufadienolides from Venenum Bufonis, a traditional Chinese medicine, displayed inhibitory effects on the growth of human HepG2 hepatocarcinoma cells and human R-HepG2 multidrug hepatocarcinoma cells. One of them, bufotalin, was also able to significantly inhibit the growth of human R-HepG2 cells xenografted into immunodeficient mice, without observing any life-threatening toxicity in the animals. "
[Show abstract][Hide abstract] ABSTRACT: Cardiac glycosides, also known as cardiotonic steroids, are a group of natural products that share a steroid-like structure with an unsaturated lactone ring and the ability to induce cardiotonic effects mediated by a selective inhibition of the Na(+)/K(+)-ATPase. Cardiac glycosides have been used for many years in the treatment of cardiac congestion and some types of cardiac arrhythmias. Recent data suggest that cardiac glycosides may also be useful in the treatment of cancer. These compounds typically inhibit cancer cell proliferation at nanomolar concentrations, and recent high-throughput screenings of drug libraries have therefore identified cardiac glycosides as potent inhibitors of cancer cell growth. Cardiac glycosides can also block tumor growth in rodent models, which further supports the idea that they have potential for cancer therapy. Evidence also suggests, however, that cardiac glycosides may not inhibit cancer cell proliferation selectively and the potent inhibition of tumor growth induced by cardiac glycosides in mice xenografted with human cancer cells is probably an experimental artifact caused by their ability to selectively kill human cells versus rodent cells. This paper reviews such evidence and discusses experimental approaches that could be used to reveal the cancer therapeutic potential of cardiac glycosides in preclinical studies.
BioMed Research International 05/2014; 2014(12):794930. DOI:10.1155/2014/794930 · 3.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hepatocellular carcinoma (HCC) is a deadly form of cancer without effective chemotherapy so far. Currently only sorafenib, a multitargeted tyrosine kinase inhibitor, slightly improves survival in HCC patients. In searching for natural anti-HCC components from toad venom which is frequently used in the treatment of liver cancer in traditional Chinese medicine, we discovered that arenobufagin, a bufadienolide from toad venom, had potent antineoplastic activity against HCC HepG2 cells as well as corresponding multidrug-resistant HepG2/ADM cells. We found that arenobufagin induced mitochondria-mediated apoptosis in HCC cells, with decreasing mitochondrial potential, as well as increasing Bax/Bcl-2 expression ratio, Bax translocation from cytosol to mitochondria. Arenobufagin also induced autophagy in HepG2/ADM cells. Autophagy-specific inhibitors (3-methyladenine, chloroquine, and bafilomycin A1) or Beclin1 and Atg 5 siRNAs enhanced arenobufagin-induced apoptosis, indicating that arenobufagin-mediated autophagy may protect HepG2/ADM cells from undergoing apoptotic cell death. In addition, we observed the inhibition of PI3K/Akt/mTOR pathway by arenobufagin. Interestingly, inhibition of mTOR by rapamycin or siRNA duplexes augmented arenubufagin-induced apoptosis and autophagy. Finally, arenobufagin inhibited the growth of HepG2/ADM xenograft tumors, which were associated with PARP cleavage, LC3-II activation, and mTOR inhibition. In summary, we first demonstrated the antineoplastic effect of arenobufagin on HCC cells both in vitro and in vivo. We elucidated the underlying antineoplastic mechanisms of arenubufagin that involve crosstalk between apoptosis and autophagy via inhibition of the PI3K/Akt/mTOR pathway. This study may provide a rationale for future clinical application using arenobufagin as a chemotherapeutic agent for HCC.
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