Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Tumor hypoxia is a main obstacle for radiation therapy. To investigate whether exposure to a proton beam can overcome radioresistance in hypoxic tumor cells, three kinds of cancer cells, Lewis lung carcinoma (LLC) cells, hepatoma HepG2 and Molt-4 leukemia cells, were treated with a proton beam (35 MeV, 1, 2, 5, 10 Gy) in the presence or absence of hypoxia. Cell death rates were determined 72 h after irradiation. Hypoxic cells exposed to the proton beam underwent a typical apoptotic program, showing condensed nuclei, fragmented DNA ladders, and poly-ADP-ribose polymerase (PARP) cleavage. Fluorescence-activated cell sorter analysis revealed a significant increase in Annexin-V-positive cells. Cells treated with the proton beam and hypoxia displayed increased expression of p53, p21 and Bax, but decreased levels of phospho-Rb, Bcl-2 and XIAP, as well as activated caspase-9 and -3. The proton beam with hypoxia induced cell death in wild-type HCT116 cells, but not in a p53 knockout cell line, demonstrating a requirement for p53. As reactive oxygen species (ROS) were also significantly increased, apoptosis could also be abolished by treatment with the anti-oxidant N-acetyl cysteine (NAC). P38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) were activated by the treatment, and their respective DN mutants restored the cell death induced by either proton therapy alone or with hypoxia. In conclusion, proton beam treatment did not differently regulate cancer cell apoptosis either in normoxic or hypoxic conditions via a p53-dependent mechanism and by the activation of p38/JNK MAPK pathways through ROS.
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PMID:Proton induces apoptosis of hypoxic tumor cells by the p53-dependent and p38/JNK MAPK signaling pathways. 1902 Jul 58

Bufotalin is one of the bufadienolides isolated from Formosan Ch'an Su, which is made of the skin and parotid glands of toads. Ingestion of toad venom results in severe morbidity and high mortality. Although Ch'an Su is clinically toxic, it has been used as an important traditional Chinese medicine for heart failure and pains. In this study, bufotalin-induced apoptosis in human hepatocellular carcinoma Hep 3B cells was investigated. The results indicate that externalization of phosphatidylserine, accumulation of sub-G(1) cells, fragmentation of DNA, and formation of apoptotic bodies were observed in bufotalin-treated Hep 3B cells. The signaling pathway might be via the activation of caspase-8, increase in mitochondrial tBid, disruption of mitochondrial membrane potential, and translocation of apoptosis-inducing factor (AIF). Active caspase-8 might activate caspase-9 and caspase-3 leading to the cleavage of nuclear PARP. Presence of AIF and cleaved PARP in the nuclei might lead to DNA fragmentation. Caspase-8 inhibitor (Z-IETD) or wide-ranging caspase inhibitor (Z-VAD) significantly suppressed the bufotalin-induced apoptosis, while the anti-Fas neutralization antibody had no effect. These data suggest that bufotalin-induced apoptosis in Hep 3B cells might involve caspases and AIF.
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PMID:Involvement of caspases and apoptosis-inducing factor in bufotalin-induced apoptosis of Hep 3B cells. 1905 67

We recently established that asparanin A, a steroidal saponin extracted from Asparagus officinalis L., is an active cytotoxic component. The molecular mechanisms by which asparanin A exerts its cytotoxic activity are currently unknown. In this study, we show that asparanin A induces G(2)/M phase arrest and apoptosis in human hepatocellular carcinoma HepG2 cells. Following treatment of HepG2 cells with asparanin A, cell cycle-related proteins such as cyclin A, Cdk1 and Cdk4 were down-regulated, while p21(WAF1/Cip1) and p-Cdk1 (Thr14/Tyr15) were up-regulated. Additionally, we observed poly (ADP-ribose) polymerase (PARP) cleavage and activation of caspase-3, caspase-8 and caspase-9. The expression ratio of Bax/Bcl-2 was increased in the treated cells, where Bax was also up-regulated. We also found that the expression of p53, a modulator of p21(WAF1/Cip1) and Bax, was not affected in asparanin A-treated cells. Collectively, our findings demonstrate that asparanin A induces cell cycle arrest and triggers apoptosis via a p53-independent manner in HepG2 cells. These data indicate that asparanin A shows promise as a preventive and/or therapeutic agent against human hepatoma.
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PMID:Asparanin A induces G(2)/M cell cycle arrest and apoptosis in human hepatocellular carcinoma HepG2 cells. 1925 88

Ochratoxin A (OTA) is a mycotoxin currently detected in stored animal and human food supplies as well as in human sera worldwide. OTA has diverse toxicological effects; however, the most prominent one is the nephrotoxicity. The present investigation was conducted to determine the molecular aspects of OTA toxicity in cultured human hepatocellular carcinoma cells. With this aim, we have monitored the effects of OTA on (i) cell viability, (ii) heat shock protein expressions as a parameter of protective and adaptive response, (iii) oxidative damage, and (iv) cell death signaling pathway. Our results clearly showed that OTA treatment inhibits cell proliferation, downregulates Hsp 70 and Hsp 27 protein and mRNA levels, and did not induce a significant reactive oxygen species generation. We have also demonstrated a decrease in mitochondrial membrane potential, a cytochrome c release, and an activation of caspase 9 and caspase 3 in response to OTA exposure. Moreover, OTA activates p53 expression, while some of its transcriptional target genes (Bax, Bak, PUMA, and p21) were found to downregulate. According to these data, we concluded that OTA may exert an inhibitory action on the transcriptional process. Besides, oxidative damage is not a major contributor to OTA toxicity. This mycotoxin induces a mitochondrial and caspase-dependent apoptotic cell death, which seems to be mediated by p53 transcriptional independent activities.
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PMID:Toxicities induced in cultured human hepatocarcinoma cells exposed to ochratoxin A: oxidative stress and apoptosis status. 1936 35

We examined the interaction between the multikinase inhibitor sorafenib and histone deacetylase inhibitors. Sorafenib and vorinostat synergized (sorafenib + vorinostat) to kill HCT116 and SW480 cells. In SW480 cells, sorafenib + vorinostat increased CD95 plasma membrane levels and promoted death-inducing signal complex (DISC) formation, and drug toxicity was blocked by knockdown of CD95 or overexpression of cellular FLICE-like inhibitory protein (c-FLIP-s). In SW620 cells that are patient-matched to SW480 cells, sorafenib + vorinostat toxicity was significantly lower, which correlated with a lack of CD95 activation and lower expression of ceramide synthase 6 (LASS6). Overexpression of LASS6 in SW620 cells enhanced drug-induced CD95 activation and enhanced tumor cell killing, whereas knockdown of LASS6 in SW480 cells suppressed CD95 activation. Knocking down LASS6 expression also suppressed CD95 activation in hepatoma, pancreatic, and ovarian cancer cells. In HCT116 cells, sorafenib + vorinostat treatment caused DISC formation without reducing c-FLIP-s expression and did not increase CD95 plasma membrane levels; sorafenib + vorinostat exposure killed HCT116 cells via an intrinsic pathway/caspase 9-dependent mechanism. In HCT116 cells, knockdown of CD95 enhanced sorafenib + vorinostat lethality, which correlated with less drug-induced CD95-dependent autophagy. Sorafenib + vorinostat treatment activated the c-Jun NH(2)-terminal kinase pathway, which was causal in promoting dissociation of Beclin1 from BCL-2, and in promoting autophagy. Knockdown of Beclin1 expression blocked autophagy and enhanced drug toxicity. Our data demonstrate that treatment of colon cancer cells with sorafenib + vorinostat activates CD95 via de novo ceramide synthesis that promotes viability via autophagy or degrades survival via either the extrinsic or intrinsic pathways.
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PMID:Sorafenib and vorinostat kill colon cancer cells by CD95-dependent and -independent mechanisms. 1948 4

We previously established a line of phosphatidylethanolamine N-methyltransferase 2 (pemt2) -stably transfected CBRH-7919 hepatoma cells, and showed that pemt2 over-expression inhibited cell proliferation and induced apoptosis. This study was aimed to further elucidate the cellular mechanisms leading to this apoptosis in these cells. Fatty acid compositions of phosphatidylcholine (PC) in pemt2 over-expressed cells and control cells, and the location of PC synthesized by PEMT2 pathway were analyzed with lipid extraction, high-performance thin layer chromatography, high-performance gas chromatography (HPGC), and [(3)H]-ethanolamine tracing. The effects of pemt2 over-expression on the mitochondrial membrane fluidity, the release of cytochrome C from mitochondria, and the activity of caspases were determined by Western blot. Newly synthesized PC by PEMT2 contained more acyl groups of oleic acid (P < 0.01) and was mainly located in mitochondria; pemt2 over-expression increased the mitochondrial membrane fluidity and the release of cytochrome C from the mitochondria into the cytoplasma, which in turn activated caspase-9 and caspase-3, the key molecules in the mitochondrial apoptotic pathway. We demonstrated that, in rat hepatoma cells, PEMT2-induced apoptosis proceeds through mitochondria.
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PMID:Over-expression of pemt2 into rat hepatoma cells contributes to the mitochondrial apoptotic pathway. 1951 28

The aim of this study was to investigate the effects of (-)-epigallocatechin-3-gallate (EGCG) on the induction of apoptosis in hepatocarcinoma cell lines in vitro and further examine the molecular mechanisms of EGCG-induced apoptosis. In the present study, it was observed that EGCG rapidly induced apoptosis in hepatocarcinoma SMMC7721 cells. EGCG-induced apoptosis was in association with the attenuation of mitochondrial transmembrane potentials (Deltapsi(m)), the alteration of Bcl-2 family proteins, the release of cytochrome c from mitochondria into the cytosol, and the activation of caspase-3 and caspase-9. Elevation of intracellular reactive oxygen species (ROS) production was also shown during EGCG-induced apoptosis of hepatocarcinoma SMMC7721 cells. The antioxidant N-acetyl-l-cysteine (NAC) significantly reduced ROS production and EGCG-induced apoptosis, suggesting that ROS plays a key role in EGCG-induced apoptosis in hepatocarcinoma SMMC7721 cells. In summary, EGCG-induced apoptosis through mitochondrial pathways, and ROS affected EGCG-induced apoptosis in hepatocarcinoma SMMC7721 cells.
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PMID:(-)-Epigallocatechin-3-gallate induces apoptosis of human hepatoma cells by mitochondrial pathways related to reactive oxygen species. 1960 28

This paper shows that the histone deacetylase inhibitor SAHA sensitised at sub-toxic doses human hepatocellular carcinoma cells (HepG2, Hep3B and SK-Hep1) to TRAIL-induced apoptosis, while it was ineffective in primary human hepatocytes (PHHs). In particular in HCC cells SAHA increased the expression of death receptor 5 (DR5) and caused a decrement of c-Flip. These two modifications provoked in the presence of TRAIL the rapid production of TRAIL-DISC and the activation of caspase-8. Consequently SAHA/TRAIL combination induced many apoptotic events, such as a cleavage of Bid into tBid, dissipation of mitochondrial membrane potential, activation of caspase-3 with the consequent cleavage of both NF-kB and Akt. The decrease in NF-kB level seemed to be responsible for the reduction in the content of IAP family antiapoptotic proteins while the decrease in Akt level caused a reduction in phospho-Bad. These events led to the activation of caspase-9, which contributed to the strong apoptotic activity of TRAIL. Sensitisation of human hepatocellular carcinoma cells to TRAIL-induced apoptosis by SAHA may suggest new strategies for the treatment of liver tumours.
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PMID:The histone deacetylase inhibitor suberoylanilide hydroxamic acid sensitises human hepatocellular carcinoma cells to TRAIL-induced apoptosis by TRAIL-DISC activation. 1964

Baicalein has been reported to induce growth-inhibitory activity in vitro in human cancer cells; however, the molecular mechanism of action is not completely understood. A pharmacological dose (10-100 microM) of baicalein exerted a cytotoxic effect on human hepatoma J5 cells resulting in G2/M arrest and apoptosis. In addition to cytotoxicity in J5 cells, several apoptotic events including mitochondrial cytochrome c release, activation of caspase-9 and -3 occurred. Baicalein induced AIF and Endo G release from mitochondria indicating that baicalein stimulates apoptosis through the caspase-independent pathway, while undergoing apoptosis, there was a remarkable accumulation of G2/M cells. Also, the ratio of Bax/Bcl-2 was increased leading to changes in mitochondria membrane potential (DeltaPsim) and release of cytochrome c, whereas the baicalein-induced apoptosis was partially abrogated by pretreatment with the pan-caspase inhibitor z-VAD-fmk, the accumulation of G2/M cells remained. These results demonstrate that the cytotoxicity of baicalein in J5 cells is attributable to apoptosis mainly involving G2/M-arrest in an ER-dependent manner, via a mitochondria-dependent caspase pathway and as well as contributions of AIF and Endo G pathways.
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PMID:Mitochondrial-dependent caspase activation pathway is involved in baicalein-induced apoptosis in human hepatoma J5 cells. 1972 7

It is well known that TP53 may mediate apoptosis triggered by anticancer drugs. However, accumulating evidence indicates that TP53 may be inactivated by mutations and/or deletions in about 50% of human cancers and, as such, may lead to pronounced resistance to therapeutic agents. Thus, the development of new approaches to improve the efficiency of therapeutic agents in cancer cells harboring mutant TP53 may have a significant impact on cancer treatment. It has been reported that knockdown by RNA interference (RNAi) of p28GANK (an alias of the gene PSMD10), a novel oncogene over-expressed in hepatocellular carcinoma (HCC), can induce apoptosis in HepG2, a TP53-intact HCC cell line. Because of the high frequency TP53 mutations in HCC, it is relevant to know whether p28GANK knockdown-induced apoptosis is also operational in TP53-negative HCC cells. Here, we investigated Adsip28GANK-induced apoptosis in the TP53-negative HCC cell line Hep3B. Our results indicate that p28GANK-knockdown induces the generation of reactive oxygen species (ROS), which in turn activates p38. Since p38 can signal to Bax, its activation may lead to mitochondrial transmembrane potential (Delta psi m) loss, cytochrome c release from mitochondria to cytosol, and caspase-9 activation, eventually triggering the mitochondrial pathway of apoptosis.
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PMID:Involvement of the mitochondrial pathway in p53-independent apoptosis induced by p28GANK knockdown in Hep3B cells. 1972 10


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