The Chrysin Enhancement Mechanism Of Human Hepatoma Hepg2 Cells Sensitive To Trail

TRAIL (Tumor necrosis factor-related apoptosis-inducing ligand,), or Apo2 ligand(Apo2L), is a member of the tumor necrosis factor(TNF) superfamily. Binding to TRAILR1 or TRAILR2, TRAIL efficiently induces apoptosis in numerous tumor cell lines through multiple signal pathway but not in the majority of normal cells. Hence, TRAIL is a promising novel anticancer therapy. Since the discovery of TRAIL in 1995, TRAIL has been attracting extensive attention. However, an increasing number of publications report on a predominance of TRAIL resistance in tumor cells, especially malignant tumor cells. Some sensitive tumor cells may acquire TRAIL resistance after repeated exposure to TRAIL. Therefore, enhancing the sensitivity of tumor cells to TRAIL has been a hot area in antitumor research.Chrysin (5,7-dihydroxyflavone) is a natural flavonoid presented in many plants, honey, and propolis. It's the major effective components of propolis. Chrysin has multiple pharmacological activities, such as anti-oxidation, anti-virus and anti-inflammation effect.In the present study, we investigated the effect of chrysin to cooperate with TRAIL to induce apoptosis of human hepatocellular carcinoma HepG2 cells, human acute leukemia Jurkat T cells and human cervical carcinoma HeLa cells. We further explored the possible mechanism of chrysin to enhance the apoptosis-inducing potential of TRAIL in HepG2 cells. The results show that chrysin significantly down-regulated the expression of IAP family member, including c-IAP1,cIAP2,XIAP and Survivin, as well as anti-apoptotic proteins of Bcl-2 family, such as Bcl-2 and Mcl-1 in HepG2 cells. In addition, chrysin effectively decreased the levels of phosphorylated Akt, phosphorylated STAT3 and phosphorylated JNK-1/2 in HepG2 cells, thus weakening the survival signals and strengthening apoptotic effect in cells.Chrysin exhibited no cytotoxic effect on nomal hepatocyte L-02 cells nor enhanced the apoptotic effect of TRAIL in L-02 cells, showing excellent tolerance. So, chrysin has great potential for cancer prevention and therapy. Defective apoptosis represents a major causative factor in the development and progression of cancer. The ability of tumor cells to evade engagement of apoptosis can play a significant role in their resistance to conventional therapeutic regimens. Therefore, induction of apoptosis in cancer cells is one of the strategies of anticancer therapy. Over the past decades, much effort has been invested into the search for agents that can differentially induce apoptotic death in cancer cells.Escin, a natural mixture of triterpene saponins extracted from dry ripe fruit of the traditional Chinese medicine Fructus Aesculi collected from a China dispensatory, and from dry ripe fruits of horse chestnut crude drug collected from Pharmacopoeia Germanica abroad, consists of A, B, C and D escin. Escin sodium was launched in 1994 in China and the indication for its use was edema that had resulted from trauma or an operation. Escin sodium has been used in clinic as anti-oedematous, anti-exudative and vasoprotective agent for many years and has shown excellent tolerability. The major mechanisms of escin sodium in the treatments of chronic venous insufficiency (CVI) and oedema have been well clarified. However, few reports focus on the anti-cancer effects of escin sodium. Mechanisms of escin sodium inhibited growth have never been investigated in human acute leukemia Jurkat T cells.Accordingly, in the present study, we investigated escin sodium exerts cytotoxic effect on human acute leukemia Jurkat T cells via the induction of apoptosis rather than cell cycle arrest and suggest a possible mechanism of escin sodium-induced apoptosis. The results of the MTT cell viability assay showed that escin sodium exhibited potent concentration-and time-dependent anti-proliferative effects in Jurkat cells. The apoptotic effects were analysed by Hoechst 33258 staining, DNA fragmentation assay, and Annexin V-FITC/PI (propidium iodide) staining assay. Morphological evidence of apoptosis, a significant increase of Annexin V+ and PI- cells (early apoptotic) and apoptotic DNA fragmentation, were observed in cells treated with escin sodium. Escin sodium activated the initiator caspase-8,-9, and the effector caspase-3, degraded poly (ADP-ribose) polymerase (PARP), and attenuated the expression of Bcl-2. In addition, escin sodium inhibits the growth of cancer cells in a selective manner with Jurkat cells most sensitive to it. These results indicate that escin sodium is a potent natural inhibitor of proliferation and inducer of apoptosis in Jurkat cells. Taken together, our data show that escin sodium possesses potent apoptogenic activity toward human acute leukemia Jurkat T cells.