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)

Effects of various stresses were examined on the accumulation of mRNA for microsomal heme oxygenase and a heat shock protein, hsp70, in three human hepatoma cell lines. By heat shock, hsp70 mRNA was induced in all three hepatoma lines, Hep G2, Hep 3B and Hep G2f, while heme oxygenase mRNA was increased only in Hep 3B. Time-courses of the heat shock induction of both mRNAs in Hep 3B were similar. Arsenite caused induction of both mRNAs in all three cell lines, while cadmium increased them in Hep G2 and Hep 3B, but not in Hep G2f cells. These findings suggest that, although both hsp70 and heme oxygenase are heat shock proteins, the mode of induction of mRNAs for these proteins is different.
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PMID:Activation of heme oxygenase and heat shock protein 70 genes by stress in human hepatoma cells. 215 80

In this study we compared sensitization to x-rays by heat or sodium arsenite and the effect of an induced heat or arsenite resistance on radiosensitization. Treatment of Reuber H35 hepatoma cells with either heat or arsenite causes a dose-dependent radiosensitization. Based on a comparison of isosurvival doses for arsenite and heat, arsenite causes a stronger enhancement of the radiosensitivity. Radiosensitization increases exponentially with increasing sensitizer dose. It is gradually lost when the time interval between irradiation and treatment with heat or arsenite increases, depending on the treatment sequence. For x-rays prior to heat, radiosensitization disappears approximately twice as fast as in the reverse case. Arsenite radiosensitization shows approximately the same kinetics for an isoeffective combination, but slightly longer times are needed for the complete clearance of the interaction. As with heat, an exposure to arsenite induces a stress response in cultured cells which results in the development of an increased tolerance towards a second exposure. Heat and arsenite induce self- as well as cross-tolerance. The reduction in arsenite or heat toxicity in tolerant cells is correlated with a reduction in radiosensitization. The mechanisms for heat and arsenite cytotoxicity appear to be different. A combination of non-toxic doses of heat and arsenite has a synergistic effect on the cytotoxicity. One hour incubation with 0.02 mM arsenite at 41 degrees C has the same cytotoxicity as 0.2 mM after 3 h incubation at 37 degrees C, and the amount of radiosensitization induced by these treatments is approximately the same.
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PMID:Sensitization to x-rays by sodium arsenite or heat in normal cells and in cells with an induced tolerance for heat and arsenite. 748 Jun 32

AIM:To study the effect of a varying concentrations of arsenic trioxide on human hepatoma cell line BEL-7402 cultured in vitro and its mechanism of action.METHODS:The BEL-7402 cells were treated with arsenic trioxide (at the concentrations of 0.5 1 2&mgr;mol/L, respectively) for 4 successive days. The cell growth and proliferation were observed by cell counting and cell-growth curve. Morphologic changes were studied with electronmicroscopy. Flow cytometry was used to assay cell-DNA distribution and the protein expression of Bcl-2 and Bax detected by immunocytochemical method.RESULTS:The cell growth was significantly inhibited by varying concentrations of arsenic trioxide as revealed by cell counting and cell-growth curve, which was dose- and time-dependent. Arsenic trioxide treatment at 0.5, 1 and 2&mgr;mol/L resulted in a sub-G1 cell peak, the apoptosis rate of the control group was 9.31% and that of 0.5&mgr;mol/L arsenic trioxide 15.53%, no significant difference was seen between the two.The apoptosis rates of 1,2&mgr;mol/L arsenic trioxide were 19.10% and 21.87% respectively, which were much higher (both P < 0.05). Decrease of G(0)/G(1) phase cells and increase of S phase cells were observed by flow cytometry, suggesting the inhibition effect of 0.5, 1, 2&mgr;mol/L arsenic trioxide on BEL-7402 cell lay in the G(0)/G(1) phase. Morphologic changes such as intact cell membrane, nucleic condensation, apoptotic body formation were seen under transmission electronmicrescopy, whereas the 0.5mol/L arsenic trioxide-treated BEL-7402 cells showed decrease of nucleocytoplasmic ratio, round nucleus, well-differentiated organelles in the cytoplasm. The processes and microvilli on the cell surface of the experimental groups under scanning electron microscopy were significantly decreased. High expressions of Bcl-2 and Bax were detected in 1 and 2&mgr;mol/L arsenic trioxide-treated cells, these were 46%, 87.33% and 83.08%, 95.83% respectively, among which that of Bax was more significant. Arsenic trioxide treatment at 0.5&mgr;mol/L resulted in a higher expression level of Bcl-2 and lower expression level of Bax,which were 8.81% and 3.83% respectively, as compared with that of the control group (15.33%) (P(1)<0.01, P(2)<0.01).CONCLUSION:Arsenic trioxide not only inhibited proliferation but also induced apoptosis of human hepatoma cell line BEL-7402. The induced-apoptosis effect of 1,2&mgr;mol/L arsenic trioxide was related to the expression level of Bcl-2 and Bax.
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PMID:Effect of arsenic trioxide on human hepatoma cell line BEL-7402 cultured in vitro. 1181 74

Arsenic trioxide (As(2)O(3)), a major ingredient of Traditional Chinese Medicine (TCM), is found to be an effective anticancer drug in acute promyelocytic leukemia (APL). The present study explored the use of As(2)O(3) on human hepatocellular carcinoma by in vitro study. The study showed that the clinically achievable concentration of As(2)O(3), i.e. 2 microM, inhibited the cell proliferation of human hepatocellular carcinoma cell line, HepG2, in a time-dependent manner. The mechanistic study showed that 2 microM of As(2)O(3) acted through induction of apoptosis in which caspase-3 was activated. The results also suggested that mitochondria did not take part in As(2)O(3)-induced apoptosis.
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PMID:Effect of arsenic trioxide on human hepatocellular carcinoma HepG2 cells: inhibition of proliferation and induction of apoptosis. 1203 46

Arsenic trioxide (As(2)O(3)) has been shown to be effective for treatment of patients with refractory or relapsed acute promyelocytic leukemia and a variety of other malignant hematopoetic disorders. We studied the effect of this agent on proliferation of human hepatoma-derived cell lines (SK-Hep-1, HepG2, and HuH7). In HuH7 cells, As(2)O(3) reduced proliferation time- and dose-dependently at 1 and 2 microM, while in SK-Hep-1 and HepG2 cells, As(2)O(3) inhibited proliferation at 2 and 4 microM respectively. Cell cycle analysis by flow cytometry showed that As(2)O(3) induced apoptosis in these hepatoma-derived cells as confirmed by appearance of sub-G(1) cells. Sensitivity of hepatoma-derived cells to As(2)O(3) was inversely related to their intracellular glutathione (GSH) and intensity of GSH synthesis. Arsenic sensitivity was restored to relatively resistant cell lines when GSH was depleted by L-buthionine sulfoximine (BSO). These results indicate that As(2)O(3) may have therapeutic potential for treatment of hepatocellular carcinoma.
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PMID:Inhibition by arsenic trioxide of human hepatoma cell growth. 1206 89

The mechanism of heme oxygenase-1 (ho-1) gene activation by arsenite was examined. Arsenite-stimulated expression of a ho-1 promoter/luciferase chimera in a dose-dependent manner in mouse hepatoma (Hepa) cells. Mutation analyses identified the arsenite-responsive sequence as the stress-response element (StRE), which resembles the binding sites for the AP-1 superfamily of basic-leucine zipper factors. In electrophoretic mobility shift assays, up to seven specific StRE-protein complexes were routinely detected using extracts from untreated Hepa cells whereas a single complex was typically observed after treatment with arsenite. Antibody "supershift" experiments identified Nrf2, JunD, and ATF3 in control complexes and the amount of these factors increased significantly in the arsenite-induced complex. MafG, ATF2, FosB, and JunB were also detected in the arsenite complex. Activation of a StRE-dependent luciferase gene by arsenite was inhibited to varying degrees by dominant-negative mutants of Nrf2, MafK, c-Fos, and CREB but most strongly with the latter. Together, these results implicate multiple basic-leucine zipper transcription factors in ho-1 gene activation by arsenite.
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PMID:Multiple basic-leucine zipper proteins regulate induction of the mouse heme oxygenase-1 gene by arsenite. 1222 May 41

Arsenic trioxide, As(2)O(3) (ATO), has been established to be an effective agent for treating acute promyelocytic leukemia, but its effect on solid tumors has not been fully explored. In the present study in a murine xenograft system, we found that ATO significantly inhibited tumor growth of the inoculated human hepatocellular carcinoma cell line HuH7 when administered either intravenously or intratumorally. Pathological examination revealed that ATO induced extensive cell death in the tumor. Some of the dead cells in intratumorally ATO-treated mice showed characteristic features of apoptosis, such as nuclear condensation and fragmentation, and were TUNEL-positive. The measurement of arsenic by using particle induced X-ray emission revealed that arsenic was accumulated more in the tumor than in brain, kidney or liver after the intravenous injection of ATO, which is consistent with the hemorrhagic cell death observed in ATO-treated tumor tissues. Thus, ATO appears to have potential for the treatment of solid tumors, as well as hematopoietic malignancies.
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PMID:Antitumor effect of arsenic trioxide in murine xenograft model. 1461 80

Arsenic trioxide (As(2)O(3)), a valuable anticancer drug for the treatment of acute promyelocytic leukemia, may also have therapeutic potential for the treatment of solid tumors. However, its therapeutic efficacy against solid tumors is lacking even at high dosages. Other therapeutic strategies are required to enhance the efficacy of As(2)O(3) against solid tumors such as hepatocellular carcinoma (HCC), which is refractory to chemotherapy. B7H3, a new member of the B7 family, has been shown to induce antitumor immunity. Intratumoral injection of B7H3 plasmids eradicates small EL-4 lymphomas, but monotherapy is ineffective against large tumors. Here we investigated whether As(2)O(3) would synergize with B7H3 immunotherapy to combat HCC. Large subcutaneous H22 HCCs (0.7-0.8 cm in diameter) established in BALB/c mice were rapidly and completely eradicated when intratumoral administration of As(2)O(3) was preceded by in situ gene transfer of B7H3. In contrast, neither As(2)O(3) nor B7H3 monotherapy was effective. The antitumor activity of As(2)O(3) was attributed to increased tumor-cell apoptosis, perhaps as a result of direct cytotoxicity as well as decreased tumor angiogenesis. Combination therapy generated potent systemic antitumor immunity mediated by CD8(+) and NK cells that was effective in combating a systemic challenge of 1 x 10(7) parental H22 cells. It led to the simultaneous and complete regression of multiple distant tumor nodules, concomitant with increased levels of serum IFN-gamma and cytotoxic T lymphocyte (CTL) activity. In conclusion, combining B7H3-mediated immunotherapy with As(2)O(3) warrants investigation as a therapeutic strategy to combat HCC, and other malignancies.
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PMID:Arsenic trioxide synergizes with B7H3-mediated immunotherapy to eradicate hepatocellular carcinomas. 1621 49

Arsenic trioxide (As2O3) is a potent antitumor agent used to treat acute promyelocytic leukemia (APL) and, more recently, solid tumors. However, the dose of As2O3 required to suppress human xenographs in mice is markedly higher than that used to treat APL in humans. Paradoxically, low doses of As2O3 stimulate angiogenesis, which might be expected to promote tumor growth. Clearly, appropriate dosages of As2O3 are required to treat human patients to avoid toxicity and undesirable side effects. In the present study, we investigated As2O3 with respect to its toxicity and effects on tumor growth, angiogenesis and cell apoptosis using H22 hepatocellular carcinoma (HCC) cells in a mouse model of HCC. As2O3 inhibited tumor growth and angiogenesis, and enhanced tumor cell apoptosis at doses greater than 1 mg/kg, but mice lost weight and failed to thrive at doses of 4 mg/kg and greater. In contrast, low doses (<1 mg/kg) of As2O3 promoted tumor growth, upregulated the expression of vascular endothelial growth factor and tumor angiogenesis, and had no effect on tumor cell apoptosis. In vitro studies demonstrated that As2O3 inhibited the proliferation of H22 tumor cells and bovine aortic endothelial cells, and induced their apoptosis in a dose- and time-dependent fashion, suggesting that the mechanism of As2O3-mediated inhibition of tumor growth is due to direct effects of the drug on both tumor cells and endothelia. In summary, different doses of As2O3 have opposing effects on tumor growth and angiogenesis. The results demonstrate that As2O3 has a narrow window of therapeutic opportunity with respect to dosage, and that low doses of the drug as used in metronomic therapy should be used with extreme caution.
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PMID:Opposing effects of arsenic trioxide on hepatocellular carcinomas in mice. 1682 9

Arsenic trioxide (As2O3) is highly efficacious in acute promyelocytic leukemia (APL). Aquaglyceroporin 9 (AQP9) is a transmembrane protein that may be involved in arsenic uptake. In 10 of 11 myeloid and lymphoid leukemia lines, quantitative polymerase chain reaction (Q-PCR) and Western blotting showed that AQP9 expression correlated positively with As2O3-induced cytotoxicity. As a proof-of-principle, transfection of EGFP-tagged AQP9 to the hepatoma line Hep3B, not expressing AQP9 and As2O3 insensitive, led to membrane AQP9 expression and increased As2O3-induced cytotoxicity. Similarly, the chronic myeloid leukemia line K562 expressed low levels of AQP9 and was As2O3 insensitive. The K562(EGFP-AQP9) transfectant accumulated significantly higher levels of intracellular arsenic than control K562(EGFP) when incubated with As2O3, resulting in significantly increased As2O3-induced cytotoxicity. Pretreatment of the myeloid leukemia line HL-60 with all-trans retinoic acid (ATRA) up-regulated AQP9, leading to a significantly increased arsenic uptake and As2O3-induced cytotoxicity on incubation with As2O3, which might explain the synergism between ATRA and As2O3. Therefore, AQP9 controlled arsenic transport and might determine As2O3 sensitivity. Q-PCR showed that primary APL cells expressed AQP9 significantly (2-3 logs) higher than other acute myeloid leukemias (AMLs), which might explain their exquisite As2O3 sensitivity. However, APL and AML with maturation expressed comparable AQP9 levels, suggesting that AQP9 expression was related to granulocytic maturation.
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PMID:Relationship of expression of aquaglyceroporin 9 with arsenic uptake and sensitivity in leukemia cells. 1696 95


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