INHIBITORY EFFECT OF TETRAMETHYLPYRAZINE ON HEPATOCELLULAR CARCINOMA: POSSIBLE ROLE OF APOPTOSIS AND CELL CYCLE ARREST.
Jianguo CaoQing MiaoJ ZhangSong MiaoLong BiS ZhangQian YangXuanxuan ZhouMingming ZhangYihu XieS Wang
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Hepatocellular carcinoma (HCC) is the fifth most common cancer. An important approach to control HCC is chemoprevention. This study aims at investigating the antitumor effect of Tetramethylpyrazine (TMP). Rats were injected with N-Nitrosodiethylamine (DEN) to establish HCC. Tumor development was observed. Liver function was evaluated. Apoptosis and cell cycle arrest-related makers and signaling cascades were determined by Western blot, RT-PCR and flow cytometric analysis. The administration of TMP could significantly inhibit tumor development in DEN-induced HCC rats, shown by reduced incidence of tumor, decreased number of tumor nodules and reduced maximal size of tumor. DEN-induced increase of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase and alkaline phosphatase activities were significantly inhibited by TMP. TMP exhibited inhibitory effect on HCC through induction of apoptosis and cell cycle arrest in rats. TMP induced apoptosis through increasing Bax, decreasing Bcl-2, increasing the release of cytochrome c, and activating caspase, which consisted of the mitochondrial apoptotic pathway. TMP induced G2/M cell cycle arrest through down-regulation of cyclin B1/cdc2. In addition, inhibition of Akt and ERK signaling and the antioxidant activities of TMP may also contribute to its antitumor effect. These data provide new insight into the mechanisms underlying the antitumor effect of TMP.Keywords:
Tetramethylpyrazine
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Cochinchina momordica seeds are a kind of traditional Chinese herb. In this study, anticancer activity and underlying mechanisms were investigated with an extract using human breast cancer MDA-MB-231 cells. The survival rate was reduced in a concentration- and time-dependent manner as assessed by MTT assay. After incubation for 48 h, typical apoptotic morphological changes were observed by Hoechst 33258 dye assay. Flow cytometry revealed that the treatment obviously induced G2/M arrest and apoptosis in MDA-MB-231 cells. Furthermore, western blotting demonstrated downregulation of protein expression of PI3K, Akt, NF-kB, Bcl-2, Cdk1 and cyclin B1, whereas Bax and caspase-3 were upregulated. Our results suggest that the extract induced cell cycle G2/M arrest and apoptosis in MDA-MB-231 cells by decreasing PI3K/Akt pathway. Therefore, we propose that ECMS has potential as a breast cancer chemotherapeutic agent.
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To explore the effects of Osthole on the proliferation, cell cycle and apoptosis of human lung cancer A549 cells.Human lung cancer A549 cells were treated with Osthole at different concentrations. Cell proliferation was measured using the MTT assay. Cell cycle was evaluated using DNA flow cytometry analysis. Induction of apoptosis was determined by flow cytometry and fluorescent microscopy. The expressions of Cyclin B1, p-Cdc2, Bcl-2, Bax, t-Akt and p-Akt were evaluated by Western blotting.Osthole inhibited the growth of human lung cancer A549 cells by inducing G2/M arrest and apoptosis. Western blotting demonstrated that Osthole down-regulated the expressions of Cyclin B1, p-Cdc2 and Bcl-2 and up-regulated the expressions of Bax in A549 cells. Inhibition of PI3K/Akt signaling pathway was also observed after treating A549 cells with Osthole.Our findings suggest that Osthole may have a therapeutic application in the treatment of human lung cancer.
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The treatment of human hepatocellular carcinoma (HCC) cell lines with (+)-isocorydine, which was isolated and purified from Papaveraceae sp. plants, resulted in a growth inhibitory effect caused by the induction of G2/M phase cell cycle arrest and apoptosis. We report that isocorydine induces G2/M phase arrest by increasing cyclin B1 and p-CDK1 expression levels, which was caused by decreasing the expression and inhibiting the activation of Cdc25C. The phosphorylation levels of Chk1 and Chk2 were increased after ICD treatment. Furthermore, G2/M arrest induced by ICD can be disrupted by Chk1 siRNA but not by Chk2 siRNA. In addition, isocorydine treatment led to a decrease in the percentage of CD133+ PLC/PRF/5 cells. Interestingly, isocorydine treatment dramatically decreased the tumorigenicity of SMMC-7721 and Huh7 cells. These findings indicate that isocorydine might be a potential therapeutic drug for the chemotherapeutic treatment of HCC.
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Our previous study successfully identified that 3,3'-Dimethylquercetin (DMQ) acted as a potent anticancer agent against human colon cancer cell lines RKO. Thus, this study was conducted to investigate the underlying mechanism by which DMQ displayed inhibitory activity in RKO cells.Flow cytometry was used to evaluate the effect of DMQ on the cell cycle arrest, as well as the mitochondrial membrane potential in RKO cells. DAPI staining and DNA fragmentation ladder assays were performed to assess the apoptosis inducing activity of DMQ. Furthermore, western blot analysis was conducted to examine the expression of related proteins responsible for the cell cycle arrest and apoptosis.Treatment with DMQ caused a significant increase in the fraction of G2/M cells, and induced remarkable apoptosis. Furthermore, western blot analysis showed that DMQ arrested cells at G2/M checkpoint by down-regulation of cyclin B1, cdc2 and cdc25c and up-regulation of p21, and induced cell apoptosis via affecting the ratio of Bax/Bcl-2, causing loss of the mitochondrial membrane potential and enhancing the expression of cleaved caspase-9 (C-caspase-9) and cleaved caspase-3 (C-caspase-3).These data showed that DMQ could suppress RKO cell growth by arresting RKO cells at G2/M checkpoint and inducing mitochondria-dependent cell apoptosis. Our findings shed light on the potential use of DMQ as a chemotherapeutic agent for CRC.
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Colorectal carcinoma (CRC) is one of the most common and aggressive malignant carcinomas. There is a pressing need to develop naturally derived novel drugs with minimal side effects for treatment of CRC. In this study, we aimed to investigate the anticancer effects of harmine hydrochloride (HMH), a hydrophilic and stable substance that is easily absorbed by tissues and similar to harmine, and the underlying mechanism of action in human CRC HCT116 cells. HMH inhibited the growth, colony formation, and migration ability of HCT116 cells. Additionally, HMH induced G2 cell cycle arrest by reducing expression of p-cdc2, cdc2, and cyclin B1, proteins that regulate the G2/M phase, and expression of Rb, a protein that regulates cell proliferation, in a dose-dependent manner. HMH mediated apoptosis by downregulating expression of apoptotic proteins (such as caspase-3, caspase-9, and PARP) and the anti-apoptotic protein Bcl-2 and by inducing expression of Bax, a pro-apoptotic protein. Furthermore, HMH reduced the levels of p-ERK, p-PI3K, p-AKT, and p-mTOR in HCT116 cells, and significantly inhibited p-ERK and p-AKT expression in cells treated with of HMH and PD98059, an ERK inhibitor, or LY294002, an AKT inhibitor (P<0.05 and P<0.01). These results demonstrate the inhibi-tory effect of HMH on cell proliferation and migration through inducing apoptosis by inhibiting ERK and PI3K/AKT/mTOR signaling pathways, indicating its potential therapeutic applications in CRC.
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Berberine Induces Cell Cycle Arrest and Apoptosis in Human Hepatocelluar Carcinoma Hep G_2 Cell Line
Objective: To study the inhibiting effects of berberine on human hepatocelluar carcinoma cell line HepG2 and the molecular mechanism.Methods: HepG2 cells were incubated with berberine at various concentration and time,cell growth inhibition was assessed by Sulphorhodamine assay,cell-cycle and apoptosis were analyzed by flow cytometry.Caspase-3,CyclinB1,CDC2 and CDK4 proteins expressions were also assessed by flow cytometry.Results: The growth of HepG2 cells was significantly inhibited by berberine in a dose-dependent and time-dependent manner.A concentration-dependent decrease of cell in G0/G1 phase and increase in S and G2/M phase were detected which was associated with an increased expression of CDC2 proteins and decreased expression of Cyclin B and CDK4 proteins.A concentration-dependent increase of cell apoptosis was detected which was associated with a marked increment of the expression of Caspase-3 proteins.Conclusion: Berberine may arrest HepG2 cells in S and G2/M phase of cell cycle through inhibiting CyclinB and CDK4 and increasing CDC2 expression.Berberine may induce HepG2 cells apoptosis through increasing the level of Caspase-3.
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