Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tamoxifen has been used in patients with hepatocellular carcinoma (HCC). However, its inhibitory mechanism remains unknown. In current study, we evaluated the effect of tamoxifen on the estrogen receptor-alpha-negative HCC cell proliferation, apoptosis and expression of survivin which had been known to play an important role in promotion of cellular proliferation as well as inhibition of apoptosis in cancer cells. HepG2 cells were incubated with tamoxifen (0.1, 1, 10, or 20 microM) for up to 72 h. Cell proliferation was assessed, flow cytometric analysis was performed, and survivin expression was detected. Our results are showed as follows. Ten or 20 microM tamoxifen induced a reduction of cell proliferation. Basically reduction of proliferation was related to an increase in the fraction of G0/1-phase. When tamoxifen was administrated at higher concentration (20 microM), the increase of the relative apoptosis appeared with a delay, augmenting the effect of tamoxifen on cell proliferation. When apoptosis was induced, a significant depression of survivin expression preceded. In conclusion, the tamoxifen decreasing cell proliferation and induction of apoptosis of HepG2 cells depends on drug concentration, which is due to cytostatic and cytocide effects, the latter may be mediated by a down-regulation of survivin expression.
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PMID:Tamoxifen inhibits proliferation and induces apoptosis in human hepatocellular carcinoma cell line HepG2 via down-regulation of survivin expression. 1899 26

It has recently been shown that cannabinoids induce growth inhibition and apoptosis in different tumour cell lines. In the current study, the effects of WIN 55,212-2 (WIN), a synthetic and potent cannabinoid receptor agonist, are investigated in hepatoma HepG2 cells and a possible signal transduction pathway is proposed. In these cells, WIN induces a clear apoptotic effect which was accompanied by up-regulation of the death-signalling factors Bax, Bcl-X(S), t-Bid and down-regulation of the survival factors survivin, phospho-AKT, Hsp72 and Bcl-2. Moreover, WIN-induced apoptosis is associated with JNK/p38 MAPK pathway activation and mitochondrial depolarisation demonstrated by a cytofluorimetric assay. The results also show that in HepG2 cells WIN markedly increases the level of the transcription factor PPARgamma in a dose- and time-dependent manner. The addition of the PPARgamma antagonists GW9662 and T0070907 significantly reduces the effects of the drug on both cell viability and the levels of survivin, phospho-AKT and phospho-BAD, suggesting that PPARgamma plays a key role in WIN-induced apoptosis. Altogether, the results seem to indicate a potential therapeutic role of WIN in hepatic cancer treatment.
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PMID:Apoptosis induced in HepG2 cells by the synthetic cannabinoid WIN: involvement of the transcription factor PPARgamma. 1905 57

Ursolic acid (UA), a naturally occurring pentacyclic triterpene, is a potent in-vitro anticancer agent, acting through control of growth, apoptosis and differentiation. As the mechanism of its proapoptotic effects on human hepatocellular carcinoma cells has not been extensively studied, we performed an in depth evaluation of the effects of UA on apoptosis in human HepG2 cells. UA was found to inhibit the proliferation of HepG2 cells in a concentration and time-dependent manner. After treatment, cells showed evidence of activation of apoptosis, including the presence of apoptotic bodies and DNA fragmentation. UA-induced apoptosis was accompanied by a significant decrease in bcl-2 and survivin expression, with the corresponding ratio of bax/bcl-2 increased. The treatment with UA also increased the protein level and enzymatic activity of caspase-3. Z-DEVD-fmk, a specific caspase-3 inhibitor, significantly inhibited both the cytotoxic effect and the DNA fragmentation induced by UA, demonstrating the requirement for caspase-3 activity in UA-induced apoptosis. Inactivation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway was also involved, as inhibition of PI3K by LY294002 significantly increased UA-induced apoptosis. Kinetic experiments indicated that UA downregulated PI3K/p85 subunit (PI3K/p85) and phospho-Akt, before downregulating survivin. The further results also confirmed that LY294002 not only downregulated survivin alone, but considerably enhanced the repression of survivin combined with UA. UA therefore seemed to downregulate the expression of survivin by blocking PI3K/Akt. Taken together, the data suggest that the proapoptotic effect of UA on HepG2 cells is mediated by activation of caspase-3, and is highly correlated with inactivation of PI3K/Akt/survivin pathway.
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PMID:Downregulation of survivin and activation of caspase-3 through the PI3K/Akt pathway in ursolic acid-induced HepG2 cell apoptosis. 1917 95

Hepatocellular carcinoma (HCC) is a major health problem, being the sixth most common cancer world-wide. Dysregulation of the balance between proliferation and cell death represents a pro-tumorigenic principle in human hepatocarcinogenesis. This review updates the recent relevant contributions reporting molecular alterations for HCC that induce an imbalance in the regulation of apoptosis. Alterations in the expression and/or activation of p53 are frequent in HCC cells, which confer on them resistance to chemotherapeutic drugs. Many HCCs are also insensitive to apoptosis induced either by death receptor ligands, such as FasL or TRAIL, or by transforming growth factor-beta (TGF-beta). Although the expression of some pro-apoptotic genes is decreased, the balance between death and survival is dysregulated in HCC mainly due to overactivation of anti-apoptotic pathways. Indeed, some molecules involved in counteracting apoptosis, such as Bcl-X(L), Mcl-1, c-IAP1, XIAP or survivin are over-expressed in HCC cells. Furthermore, some growth factors that mediate cell survival are up-regulated in HCC, as well as the molecules involved in the machinery responsible for cleavage of their pro-forms to an active peptide. The expression and/or activation of the JAK/STAT, PI3K/AKT and RAS/ERKs pathways are enhanced in many HCC cells, conferring on them resistance to apoptotic stimuli. Finally, recent evidence indicates that inflammatory processes, as well as the epithelial-mesenchymal transitions that occur in HCC cells to facilitate their dissemination, are related to cell survival. Therefore, therapeutic strategies to selectively inhibit anti-apoptotic signals in liver tumor cells have the potential to provide powerful tools to treat HCC.
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PMID:Dysregulation of apoptosis in hepatocellular carcinoma cells. 1919 51

Glypican-3 (GPC-3), a membrane-anchored heparin sulfate proteoglycan, has been shown to be expressed in approximately 80% of hepatocellular carcinoma (HCC) but not in benign hepatic lesions. Survivin, a novel inhibitor of apoptosis, and a prognostic marker, has also been expressed in HCC. We evaluated these two immunomarkers (GPC-3 and survivin) in differentiating HCC from benign and preneoplastic hepatic lesions and metastatic carcinomas, comparing them to HepPar-1 (hepatocyte paraffin-1) in liver fine-needle aspiration biopsies (FNAB).Immunohistochemistry for GPC-3, survivin and HepPar-1 was performed on 92 FNAB including HCC, hepatic cirrhosis, focal nodular hyperplasia (FNH), hepatic adenoma, dysplastic hepatic nodules and metastatic carcinomas. Immunostaining was scored as positive, if > or =10% of tumor cells stained.GPC-3 is immunoexpressed in 56.8% of HCC, but not in benign and preneoplastic hepatic lesions, or metastatic carcinomas; whereas survivin is expressed in HCC (86.4%), benign hepatic lesions (85.7%), dysplastic hepatic nodules (100%) and metastatic carcinomas (94.3%). HepPar-1 is immunoexpressed in HCC (72.7%), benign hepatic lesions (100%), dysplastic nodules (100%) and metastatic carcinomas (2.9%). The sensitivity and specificity of GPC-3, survivin and HepPar-1 for detection of HCC are 56.8 and 100%, 86.4 and 6.3%, 72.7 and 70.8%, respectively.GPC-3 is a reliable and more specific immunohistochemical marker than survivin for the diagnosis of HCC in FNAB. HepPar-1, although a more sensitive marker than GPC-3, has a lower specificity for detection of HCC. Our data supports the potentially significant diagnostic utility of GPC-3 in FNABs in differentiating primary malignant from benign and preneoplastic liver lesions, and metastatic carcinomas.
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PMID:Utility of glypican-3 and survivin in differentiating hepatocellular carcinoma from benign and preneoplastic hepatic lesions and metastatic carcinomas in liver fine-needle aspiration biopsies. 1940 9

Hepatocellular carcinomas represent the third leading cause of cancer-related deaths worldwide. Survivin, a structurally unique member of the inhibitor of apoptosis protein (IAP) family, is overexpressed in a wide range of malignancies, including hepatocellular carcinoma. Due to its involvement in cancer progression and treatment resistance, survivin is currently undergoing extensive investigation as a novel intervention target to induce apoptosis in cancer cells by phytochemicals or synthetic agents. Brazilein, a compound obtained in a large amount from the dried heartwood of Caesalpinia sappan Linn., which has long been used in traditional medicine in China, has some pharmacological activities. Human hepatocellular carcinoma HepG2 cells were treated with brazilein and analyzed for survivin protein and mRNA levels by Western blotting and real-time RT-PCR, respectively. Brazilein treatment of cells for 48 h at 5 and 10 microg/ml doses resulted in significantly decrease in survivin protein expression. We also observed that brazilein caused a strong decrease in survivin mRNA expression. In other studies, down-regulation of survivin by brazilein was associated with a strong and prominent caspases-9 and -3 activation as well as PARP cleavage. It was also shown that brazilein induced a strong apoptotic cell death, as shown by DNA ladder assay, and growth inhibition of HepG2 cells. Further studies are needed to investigate in vivo effect of brazilein on survivin expression and associated biological effects in hepatocellular carcinoma that could provide useful information for brazilein efficacy in the prevention/intervention of human hepatocellular carcinoma.
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PMID:Brazilein inhibits survivin protein and mRNA expression and induces apoptosis in hepatocellular carcinoma HepG2 cells. 1958 Mar 39

Hepatocellular carcinoma (HCC) frequently includes abnormalities in cell cycle regulators, including up-regulated cyclin-dependent kinase (Cdks) activities due to loss or low expression of Cdk inhibitors. In this study, we show that xylocydine, a cyclin-dependent kinase (Cdk) specific inhibitor, is a good anti-cancer drug candidate for HCC treatment. Xylocydine (50muM) selectively down-regulates the activity of Cdk1 and Cdk2, accompanied by significant cell growth inhibition in HCC cells. Xylocydine also strongly inhibits the activity of Cdk7 and Cdk9, in vitro as well as in cell cultures, that is temporally associated with apoptotic cell death in xylocydine-induced HCC cells. This is associated with inhibition of phosphorylation of RNA polymerase II at serine residues 5 and 2, which are targets of Cdk7 and Cdk9, respectively. The effects on apoptosis are concomitant with changes in the levels of anti-apoptotic proteins, Bcl-2, XIAP, and survivin, which are markedly down-regulated, and pro-apoptotic molecules, p53 and Bax, which are elevated in HCC cells after treatment with xylocydine. The up-regulated level of p53 was associated with increased stability of the protein, as levels of Ser15 and Ser392 phsophorylated p53 are similarly elevated in the inhibitor treated cells. We demonstrated that xylocydine can effectively suppress the growth of HCC xenografts in Balb/C-nude mice by preferentially inducing apoptosis in the xenografts, whereas the drug did not cause any apparent toxic effect on other tissues. Taken together, these data suggest that the novel Cdk inhibitor xylocydine is a good candidate for an anti-cancer drug for HCC therapy.
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PMID:Xylocydine, a novel Cdk inhibitor, is an effective inducer of apoptosis in hepatocellular carcinoma cells in vitro and in vivo. 1961 71

Hepatocellular carcinoma (HCC) is the 5th most common cancer worldwide. It is intrinsically resistant toward standard chemotherapy, making it imperative to develop novel selective chemotherapeutic agents. The Wnt/beta-catenin pathway plays critical roles in development and oncogenesis, and is dysregulated in HCC. Our study aims to evaluate the activity of 3 small molecule antagonists of the Tcf4/beta-catenin complex (PKF118-310, PKF115-584 and CGP049090) on HCC cell lines in vitro and in vivo. All 3 chemicals displayed dose-dependent cytotoxicity in vitro against all 3 HCC cell lines (HepG2, Hep40 and Huh7), but were at least 10 times less cytotoxic to normal hepatocytes (from 3 donors) by using ATP assay. In HepG2 and Huh7 cells, treatment with the antagonists decreased Tcf4/beta-catenin binding capability and transcriptional activity, associated with downregulation of the endogenous Tcf4/ beta-catenin target genes c-Myc, cyclin D1 and survivin. In HepG2 and Huh7 cells, treatment with the antagonists induced apoptosis and cell cycle arrest at the G1/S phase. All antagonists suppressed in vivo tumor growth in a HepG2 xenograft model, associated with apoptosis and reduced c-Myc, cyclin D1 and survivin expressions. Our results suggest that these 3 antagonists of the Tcf4/beta-catenin complex are potential chemotherapeutic agents which may offer a pathway specific option for the clinical management of HCC.
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PMID:Small molecule antagonists of Tcf4/beta-catenin complex inhibit the growth of HCC cells in vitro and in vivo. 1966 54

Human hepatocellular carcinoma (HCC) is one of the most causes of cancer-related death and is well known because of resistant to chemotherapeutic drug. Co-delivery of antitumor agent docetaxel and iSur-pDNA, a suppressor of metastatic and resistance-related protein survivin, was postulated to achieve synergistic/combined effect of antitumor drug and gene therapeutics. To valid this hypothesis, a folate-modified multifunctional nanoassembly (FNA) loading both docetaxel and iSur-pDNA was constructed and evaluated as a therapeutic approach for HCC. The FNAs were prepared with folate-modified lipid FA-PEG-DSPE as the target to tumor, protamine sulfate (PS) as the condenser to protect and enhance the nuclear transfer of iSur-pDNA, and DOPE-based lipid envelope as the carrier of doctaxel and PS/DNA complex to achieve their co-delivery and enhance internalization into hepatoma cells. FNAs showed the particle size about 200nm with encapsulation efficiency >90%. Blank nanoassemblies (BNAs) loading only reporter gene revealed higher transfection efficiency with neglectable cytotoxicity compared with Lipofectamine 2000, which could result from enhanced cellular uptake via ligand-receptor recognition and efficient nuclear delivery mediated by PS. Cytotoxicity of FNAs against hepatocellular carcinoma cell line BEL 7402 was much higher than either docetaxel or non-docetaxel FNAs (nFNAs) loading only iSur-pDNA, and was also superior to the combined treatment with free docetaxel and nFNAs. Better antitumor efficacy of FNAs with low systemic toxicity was also observed on mouse hepatocellular carcinoma xenograft model. These results suggested that co-delivery of docetaxel and iSur-pDNA with FNAs could be a safer and more efficient strategy for the treatment of locally advanced and metastatic HCC.
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PMID:The characteristics and performance of a multifunctional nanoassembly system for the co-delivery of docetaxel and iSur-pDNA in a mouse hepatocellular carcinoma model. 1984 17

Abnormal high activation of survivin is involved in carcinogenesis of various types of cancer. Survivin has been shown to promote cell proliferation in human hepatocellular carcinoma (HCC). Survivin-targeting approaches have become a promising strategy for treating HCC. Here, we used a reporter system to screen effective survivin siRNA sequences. The effect of vector-based survivin short hairpin RNA (shRNA) on the malignant phenotype of HCC cells in vitro and in vivo was determined, and an adenovirus-mediated shRNA expression vector was developed to decrease survivin expression of the established HCC tumor in nude mice. In vitro study showed that stable survivin knockdown inhibited cancer cell proliferation, enhanced apoptotic susceptibility, arrested cell cycle in the G1 phase and resulted in apparent mitotic catastrophe. Moreover, cells stably expressing survivin shRNA showed decreased tumorigenicity in nude mice. An additional in vivo study showed that intratumoral injection of adenovirus-delivered survivin shRNA suppressed tumor growth by spontaneous apoptosis of cancer cells and significantly prolonged animal survival. In conclusion, we proved the therapeutic potential of survivin shRNA for the treatment of HCC. And our results indicated that adenovirus-delivered shRNA may serve as a novel therapeutic for HCC.
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PMID:Survivin knockdown by short hairpin RNA abrogates the growth of human hepatocellular carcinoma xenografts in nude mice. 1987 77


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