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)

The protein encoded by bcl-2 proto-oncogene plays an important role in the mitochondria-mediated apoptotic pathway. Although the general role of Bcl-2 is anti-apoptotic, previous work showed that Bcl-2 fragments cleaved by caspases could promote apoptotic process. We report herein that Bcl-2 protein was cleaved to produce two fragments of around 23 kDa in human hepatocarcinoma BEL-7404 cells or in Bcl-2 overexpressing CHO cells induced by cisplatin. Treating cells with the general caspase inhibitor z-VAD-fmk blocked the induced cleavage of Bcl-2. Mutagenesis analyses showed that Bcl-2 was cleaved by caspases at two adjacent recognition sites in the loop domain (YEWD(31) decrease AGD(34) decrease V), which could be inhibited by caspase-8 and -3 inhibitors, respectively. Overexpression of the carboxyl terminal 23 kDa fragments increased the sensitivity of CHO cells to cisplatin-induced apoptosis. These results indicate that Bcl-2 can be cleaved into two close fragments by different caspases during cisplatin-induced apoptosis, both of which contribute to the acceleration of apoptotic process.
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PMID:Bcl-2 cleavages at two adjacent sites by different caspases promote cisplatin-induced apoptosis. 1745 97

Antineoplaston A10 (3-phenylacetylamino-2,6-piperidinedion) is a naturally occurring substance and was the first antineoplaston in the human body to be chemically identified. The effect of antineoplaston A10 on human hepatocellular carcinoma cell lines HepG2 and HLE has been examined. Antineoplaston A10 displayed anti-proliferative action inhibiting cell growth in a dose- and time-dependent manner in vitro as measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and clonogenic assays. Incubation with antineoplaston A10 for 48 h induced apoptotic events such as a typical apoptotic morphology, formation of a characteristic ladder pattern of DNA migration and accumulation of sub-G1 phase cells. Next, hepatoma xenografts in nude mice were employed to study the antitumor effects of antineoplaston A10 in vivo. Oral administration of antineoplaston A10 delayed the growth of HepG2 and HLE cells in the mice without a reduction in body weight. A higher proportion of apoptotic cells in xenografts was observed by means of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining. In addition, the level of expression of apoptotic marker p53 increased while that of anti-apoptotic protein bcl-2 decreased, as evaluated with immunohistochemical staining in the xenografts. These results suggested that antineoplaston A10 may inhibit the growth of human hepatoma cells through the induction of apoptosis.
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PMID:Induction of apoptosis in human hepatocellular carcinoma cells by synthetic antineoplaston A10. 1769 34

Forty-six new compounds were synthesized on the basis of our knowledge of the 3-haloacylamino benzoylurea (HBU) series. Structure-activity relationship (SAR) analysis indicates that (i) the configuration of the chiral center in 1 (JIMB01) is not indispensable for the activity, (ii) the phenyl ring is essential, and (iii) a substitution at the 6-position of the phenyl ring with a halogen enhances the activity. Among the analogues, 11e and 14b bearing 6-fluoro substitution showed potent activities against nine human tumor cell lines, including CEM (leukemia), Daudi (lymphoma), MCF-7 (breast cancer), Bel-7402 (hepatoma), DU-145 (prostate cancer), PC-3 (prostate cancer), DND-1A(melanoma), LOVO (colon cancer), and MIA Paca (pancreatic cancer) with IC 50 values between 0.01 and 0.30 microM. 14b inhibited human hepatocarcinoma by 86% in volume in nude mice. The mechanism of 14b is to inhibit microtubule assembly, followed by the M-phase arrest, bcl-2 inactivation, and then apoptosis. We consider 14b promising for further anticancer investigation.
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PMID:Benzoylurea derivatives as a novel class of antimitotic agents: synthesis, anticancer activity, and structure-activity relationships. 1845 82

The effect of targeted magnetic nanoparticles on hepatoma and the underlying mechanism were examined. Nude mice transplanted with a human hepatoma cell line (HepG2 cells) were randomized into 5 groups, including: (1) group A, receiving normal saline, (2) group B, receiving 5-fluorouracil (5-Fu), (3) group C, receiving magnetic nanoparticles containing 5-Fu, (4) group D, consisting of treatment with magnetic nanoparticles containing 5-Fu and inside magnetic field and (5) group E, receiving pure magnetic nanoparticles and inside magnetic field. Morphological features of transplanted tumors in mice in each group were observed under transmission electron microscope (TEM). The expression of bcl-2/bax protein was immunohistochemically detected by SABC method. The results showed that a large number of apoptotic tumor cells were found in group B and group D under TEM. The expression of bcl-2 protein was significantly decreased and the expression of bax protein increased significantly in both group B and D as compared with those in group A, C and E (P<0.01 for all). The decrease in bcl-2 and the increase in bax were more in group D as compared with group B (P<0.01). It is concluded that the targeted magnetic nanoparticles containing 5-Fu can improve the chemotherapeutic effect of 5-Fu by decreasing bcl-2 expression, increasing bax expression and inducing apoptosis of the liver cancer cells.
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PMID:The effect of targeted magnetic nanopaticles on hepatoma and the expression of bcl-2/bax protein. 1870 8

To explore the metabolic effects of Bcl-2 in tumor cells, a stable clone of HuH-7/bcl-2 and its control HuH-7/neo were established. Mitochondrial localization of ectopic Bcl-2 was demonstrated both by western blotting and immunofluorescence. HuH-7/bcl-2 cells consumed glucose at a higher rate, exhausted the available cellular ATP and died on day 9, while HuH-7/neo cells were still alive for 10 days under the same condition where cells were cultured without replenishment of the medium. The expression of the hexokinase II gene was up-regulated in HuH-7/bcl-2 at its protein level. Taken together, we suggest that the forced expression of Bcl-2 in human hepatoma may cause the cells to become more glucose-dependent for survival.
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PMID:Enhanced Glucose Requirement in Human Hepatoma-derived HuH-7 Cells by Forced Expression of the bcl-2 Gene. 1881 43

Effective therapies for advanced stages of hepatocellular carcinoma (HCC) have yet to be developed. We investigated how far a combination of the HDAC inhibitor MS-275 and the CDK inhibitor CYC-202 synergizes to inhibit proliferation and promotes apoptosis of hepatoma cells in vitro. Human hepatoma cell lines Hep3B and HepG2 as well as primary human foreskin fibroblasts as non-malignant controls were cultured under standardized conditions and incubated with increasing concentrations of CYC-202 and MS-275 as single agents and in combination. After 24 to 72 h, apoptosis was analyzed by flow cytometry (propidium iodide, JC-1) and by immunocytochemistry for cytokeratin 18 fragmentation. DNA synthesis was assessed using bromodeoxyuridine incorporation. Protein was separated for Western blotting against p21, bax and bcl-2 and fluorimetric activity assays against caspase 3 and 8. The results showed that the combination of CYC-202 and MS-275 leads to better pro-apoptotic effects than the employment of single substances. Apoptosis was induced via the mitochondrial pathway as evidenced by a shift in the bax/bcl-2 ratio and breakdown of mitochondrial transmembrane potentials. Caspase assays revealed a strong induction of caspase 3 but not of the extrinsic initiator caspase 8. In conclusion, combination therapy with the biomodulators MS-275 and CYC-202 is a promising treatment option for HCC.
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PMID:The histone-deacetylase inhibitor MS-275 and the CDK-inhibitor CYC-202 promote anti-tumor effects in hepatoma cell lines. 1894 29

Astragalus membranaceus has been used to ameliorate the side effects of anti-neoplastic drugs. We recently reported that total Astragalus saponins (AST) possess anti-tumor properties in human colon cancer cells and tumor xenografts. Nevertheless, the precise mechanism of action has not been fully elucidated. The present study aimed to unveil the anti-carcinogenic potential of AST in HepG2 human hepatocellular carcinoma (HCC) cells and to clarify the signaling pathway. We demonstrated here that AST downregulated expression of the HCC tumor marker alpha-fetoprotein and suppressed HepG2 cell growth by inducing apoptosis. AST also caused caspase activation, poly(ADP-ribose) polymerase (PARP) cleavage, nuclear chromatin condensation, with downregulation of the anti-apoptotic proteins bcl-2 and bcl-xL and decreased nuclear factor-kappa B (NF-kappaB)/DNA-binding activity. Concomitantly, expression of the phosphorylated form of the extracellular signal-regulated protein kinase (ERK) was prominently increased. Nevertheless, pretreatment of ERK inhibitor PD98059 did not attenuate AST-induced PARP cleavage. Taken together, these results exemplify that AST induced growth inhibition and promoted apoptosis in HepG2 cells through modulation of an ERK-independent NF-kappaB signaling pathway.
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PMID:Astragalus saponins induce apoptosis via an ERK-independent NF-kappaB signaling pathway in the human hepatocellular HepG2 cell line. 1914 42

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

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a highly toxic pollutant ubiquitously present in the environment. Most of the toxic effects of TCDD are believed to be mediated by high-affinity binding to the aryl hydrocarbon receptor (AhR) and subsequent effects on gene transcription. TCDD causes cancer in multiple tissues in different animal species and is classified as a class 1 human carcinogen. In initiation-promotion studies TCDD was shown to be a potent liver tumor promotor. Among other theories it has been hypothesized that TCDD acts as a tumor promotor by preventing initiated cells from undergoing apoptosis. We examined the effects of TCDD on ultraviolet C (UV-C) light-induced apoptosis in primary rat hepatocytes and Huh-7 human hepatoma cells. TCDD inhibits UV-C light-induced apoptosis in both cell types. This effect is seen with chromatin condensation and fragmentation and appears to be mediated by the AhR in rat hepatocytes. Apoptosis induced by UV-C light in these cells is caspase-dependent and is accompanied by alterations in apoptosis-related gene expression such as up-regulation of proapoptotic bcl-2 family genes like bak and bax, and a marked down regulation of the expression of the antiapoptotic bcl-2. TCDD treatment of irradiated hepatocytes induces the expression of some apoptosis-related genes (birc3, dad1, pycard, tnf). Upstream apoptotic events, namely caspase activation and caspase substrate cleavage are not inhibited by TCDD treatment. We hypothesize that TCDD inhibits late-stage apoptotic events that lead to internucleosomal DNA fragmentation, maintaining chromosomal integrity probably in order to sustain metabolic capacity and hepatic elimination of substrates despite of an initiation of apoptosis.
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PMID:Inhibition of UV-C light-induced apoptosis in liver cells by 2,3,7,8-tetrachlorodibenzo-p-dioxin. 1952 Jun 75

Apoptin, a chicken anemia virus-derived, p53-independent, bcl-2-insenstive apoptotic protein with the ability to specifically induce apoptosis in tumor or transformed cells, is a promising tool for cancer gene therapy. In this study, pseudotype baculovirus, a recently developed alternative gene delivery system, was used as a vector to express Apoptin. The resultant recombinant baculovirus (BV-Apoptin) efficiently expressed the Apoptin protein and induced apoptosis in HepG2 and H22 cells. Studies in vivo showed that intratumoral injection of BV-Apoptin into a xenogeneic tumor (derived from H22 murine hepatoma cells in C57BL/6 mice) significantly suppressed tumor growth, and significantly prolonged the survival of tumor-bearing mice compared to a control pseudotype baculovirus that expressed EGFP. Taken together, these results suggest that Apoptin, expressed from the pseudotype baculovirus vector, has the potential to become a therapeutic agent for the treatment of solid tumors.
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PMID:Antitumor effects of a recombinant pseudotype baculovirus expressing Apoptin in vitro and in vivo. 1982 41


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