Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genotoxic stimuli, including anticancer drugs, induce apoptosis in cancer cells through increase of p53, p21WAF1/CIP1, at least in part. Bcl-2 and Bax modify this pathway or directly regulated by p53. Here we studied Adriamycin (ADM)-induced apoptosis in four human bladder cancer cell lines in respect of p53, p21WAF1/CIP1 and Bcl-2 family proteins. After ADM, treatment bladder cancer cells underwent dose-dependent cell death with typical morphologic features of apoptosis. Among four cell lines RT4 with wt p53, low ratio of Bcl-2 to Bax and induction of p21WAF1/CIP1 after ADM treatment, was the most sensitive to induction of apoptosis. Thus, p53, p21WAF1/CIP1, Bcl-2 and Bax status might determine susceptibility of bladder cancer cells to ADM induced apoptosis.
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PMID:Adriamycin (ADM) induced apoptosis in transitional cell cancer (TCC) cell lines accompanied by p21 WAF1/CIP1 induction. 1464 56

Interactions between the histone deacetylase inhibitors (HDACIs) suberoylanilide hydroxamic acid (SAHA) and sodium butyrate (SB) and the heat shock protein (Hsp) 90 antagonist 17-allylamino-17-demethoxygeldanamycin (17-AAG) have been examined in human leukemia cells (U937). Coadministration of marginally toxic concentrations of 17-AAG with sublethal concentrations of SB or SAHA resulted in highly synergistic induction of mitochondrial damage (i.e., cytochrome c release), caspase-3 and -8 activation, and apoptosis. Similar interactions were noted in human promyelocytic (HL-60) and lymphoblastic (Jurkat) leukemia cells. These events were accompanied by multiple perturbations in signal transduction, cell cycle, and survival-related pathways, including early down-regulation of Raf-1, inactivation of extracellular signal-regulated kinase (ERK) 1/2 and mitogen-activated protein/ERK kinase (MEK) 1/2, diminished expression of phospho-Akt, and late activation of c-Jun-NH(2)-terminal kinase, but no changes in expression of phospho-p38 mitogen-activated protein kinase. Coadministration of 17-AAG blocked SAHA-mediated induction of the cyclin-dependent kinase inhibitor p21(CIP1) and resulted in reduced expression of p27(KIP1) and p34(cdc2). 17-AAG/SAHA-treated cells also displayed down-regulation of the antiapoptotic protein Mcl-1 and evidence of Bcl-2 cleavage. Enforced expression of doxycycline-inducible p21(CIP1) or constitutively active MEK1 significantly diminished 17-AAG/SAHA-mediated lethality, indicating that interference with ERK activation and p21(CIP1) induction play important functional roles in the lethal effects of this regimen. In contrast, enforced expression of constitutively active Akt failed to exert cytoprotective actions. Together, these findings indicate that coadministration of SAHA or SB with the Hsp90 antagonist 17-AAG in human leukemia cells leads to multiple perturbations in signaling, cell cycle, and survival pathways that culminate in mitochondrial injury and apoptosis. They also raise the possibility that combining such agents with Hsp90 antagonists may represent a novel antileukemic strategy.
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PMID:Coadministration of the heat shock protein 90 antagonist 17-allylamino- 17-demethoxygeldanamycin with suberoylanilide hydroxamic acid or sodium butyrate synergistically induces apoptosis in human leukemia cells. 1467 5

Environmental contaminants possessing hormonal activity have long been suspected of playing a role in cancer causation. What is unclear is whether such agents elicit their effects through genotoxic and/or epigenetic mechanisms. gamma-Hexachlorocyclohexane (gamma-HCH, lindane) was tested in the 10(-12)-10(-4) M range. Chromosomal damage in MCF-7 breast cells and PC-3 prostate cells was assessed using the cytokinesis block micronucleus assay. Micronuclei (MNi) were scored in 1000 binucleate cells per treatment. Cell viability and cell cycle kinetics were also assessed, along with immunocytochemical and quantitative gene expression analyses of CDKN1A (P21WAF1/CIP1), BCL-2 and BAX. Following 24 h treatment, lindane (10(-12)-10(-10) M) induced increases (up to 5-fold) in MNi in both cell lines. Increases in MNi occurred in the absence of DNA single-strand breaks or cytotoxicity and, compared with benzo[a]pyrene and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, at low concentrations. Lindane induced more MNi than the alpha or beta stereoisomers of HCH. Low dose lindane (10(-12)-10(-10) M) significantly elevated the percentage of MCF-7 cells staining positive for Bcl-2 and of PC-3 cells staining positive for Bax. Only high dose lindane (10(-4) M) disrupted cell cycle kinetics with increases in percentage of cells in G1 and decreases in percentage of cells in G2/M. Despite a comparable high dose lindane induction of cell cycle arrest, marked increases in expression of P21WAF1/CIP1 were observed only in MCF-7 cells, although in PC-3 cells a significant increase (P < 0.0005) in the percentage of cells staining positive for p21Waf1/Cip1 was seen. These results suggest that 'environmental' concentrations of lindane can induce a number of subtle alterations in breast and prostate cells in the absence of cytotoxicity.
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PMID:Low dose induction of micronuclei by lindane. 1468 26

Interactions between histone deacetylase (HDAC) inhibitors and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), also known as Apo2 ligand, were examined in human leukemia cells (e.g., U937, Jurkat, and HL-60). Simultaneous exposure of cells to 100-ng/ml TRAIL with either 1-mM sodium butyrate or 2- micro M suberoylanilide hydroxamic acid resulted in a striking increase in leukemic cell mitochondrial damage, caspase activation, and apoptosis. Lethal effects were significantly diminished in U937 cells ectopically expressing dominant-negative caspase-8, dominant-negative Fas-associated death domain, CrmA (receptor pathway), or Bcl-2 or Bcl-X(L) (mitochondrial pathway). Analysis of mitochondrial events in U937 cells exposed to TRAIL/HDAC inhibitors revealed enhanced Bid activation and Bax translocation, loss of mitochondrial membrane potential, and cytoplasmic release of cytochrome c, Smac/DIABLO, and apoptosis-inducing factor. No changes were observed in expression of FLICE-like inhibitory protein, TRAIL receptors, or reactive oxygen species generation. TRAIL/HDAC inhibitor-induced apoptosis triggered caspase-dependent cleavage of p21(WAF1/CIP1); moreover, enforced expression of a nuclear localization signal deletant form of p21(WAF1/CIP1) significantly diminished lethality. Lastly, p27(KIP1), pRb, X-linked inhibitor of apoptosis, and Bcl-2 displayed extensive proteolysis. These findings indicate that coadministration of TRAIL with HDAC inhibitors synergistically induces apoptosis in human myeloid leukemia cells and provide further evidence that simultaneous activation of the extrinsic and intrinsic pathways in such cells leads to a dramatic increase in mitochondrial injury and activation of the caspase cascade.
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PMID:Simultaneous activation of the intrinsic and extrinsic pathways by histone deacetylase (HDAC) inhibitors and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) synergistically induces mitochondrial damage and apoptosis in human leukemia cells. 1470 68

We employed potent and selective c-Src inhibitors to investigate the functional and molecular consequences of inhibited c-Src tyrosine kinase activity in osteoclasts. These pyrrolopyrimidine derivatives reduced osteoclast numbers and induced osteoclast disruption in vivo. In vitro, they inhibited resorption pit formation and osteoclastogenesis, impaired adhesion ability and actin ring organization, and induced programmed cell death in mature osteoclasts. The cell death receptor Fas and p53 were insensitive to c-Src modulation. The expression of the cyclin-dependent kinase (CDK)-inhibitor p21WAF1/CIP1 was markedly reduced, but neither Bcl-2 nor Bcl-xL or Bax were modulated by c-Src inhibition. Caspase-9, and to a lesser extent caspase-3, but not caspase-8, were transiently cleaved (activated) by treatment with the c-Src inhibitors. c-Src inhibition stabilized p38 mitogen-activated protein kinase (MAPK), whereas the c-Jun N-terminal kinase (JNK) pathway did not appear to be modulated by our compounds. Most interestingly, transient extracellular signal regulated kinase (ERK1/2) dephosphorylation followed by sustained remarkable rephosphorylation overwhelming control levels was observed in response to c-Src inhibition. Blockade of ERK1/2 rephosphorylation by PD98059 reduced osteoclast nuclear disruption, suggesting the involvement of this pathway in apoptosis. Collectively, these data demonstrate that small pyrrolopyrimidine derivatives impair osteoclast function and induce cell damage suggestive of apoptosis in vivo and in vitro, with mechanisms presumably involving selective sustained ERK1/2 phosphorylation.
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PMID:Reduction of c-Src activity by substituted 5,7-diphenyl-pyrrolo[2,3-d]-pyrimidines induces osteoclast apoptosis in vivo and in vitro. Involvement of ERK1/2 pathway. 1475 64

Magnesium ions have been shown to be a promising treatment for brain lesions caused by traumatic brain injury (TBI), as well as for the associated acute neurodegeneration and progressive functional deficits. This study investigated the effects of magnesium on the expression of the cell death/survival related proteins following TBI. Male Sprague-Dawley (SD) rats (n = 66, 280-320 g body weight) were subjected to sham surgery alone (n = 14), or to the surgery followed by a lateral fluid percussion brain injury of moderate severity (n = 52, 2.4-2.7 atm). The injured rats were randomly treated with an intravenous bolus of magnesium chloride (n = 26, 125 micromol) or saline vehicle (n = 26). The coronal brain sections were quantitatively analyzed for cell apoptosis and the expression of p53-related proteins, Bcl-2, cyclin D1 and PCNA at 1, 2, and 4 days post-injury by immunohistochemistry or in situ hybridization. Tissue damage was observed primarily in the ipsilateral cortex of the injured region with the induction of apoptosis and p53 mRNA level at 2 days after TBI. The expression of p53 and responding proteins (p21(WAF1/CIP1), Mdm2 and Bax) showed a temporal pattern similar to the apoptotic events in the time course experiments. They were induced in the early time points of days 1-2, decreasing by day 4 after TBI. In contrast, the expression of the cell survival related proteins - Bcl-2, cyclin D1, and PCNA - was most significant at day 4 post-injury, when the rate of apoptosis decreased. Magnesium treatment resulted in a reduction in apoptosis and expression of p53-related proteins. However, it had only a slight additive effect on the expression of the survival related proteins in the same time-course. These results provide a molecular basis for the efficiency of magnesium in treating TBI-induced tissue damage.
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PMID:A molecular basis for the efficacy of magnesium treatment following traumatic brain injury in rats. 1516 63

Human parvovirus B19 has been found in various tissues in addition to erythroid lineage cells, and non-structural protein (NS1) is reported to induce cytotoxicity and apoptosis in erythroid lineage cells, but the mechanism in non-permissive cells is still unclear. To address this issue, we have constructed the NS1 gene in a cytomegalovirus episomal vector, pEGFP-C1 and transfected it into monkey epithelial cells, COS-7. EGFP-NS1 expression in transfected cells was monitored and assessed by fluorescence microscopy, RT-PCR and Western blot. The flow cytometric analysis showed that the NS1-transfected cells were arrested at G1 phase by paclitaxel treatment and there was increased apoptosis. The expression of p53, an important molecule in apoptosis and cell cycle regulation, and its downstream cell cycle kinase inhibitors p16(INK4) and p21(WAF1/CIP1) were up-regulated in the NS1-transfected cells. Also, increased expression of the pro-apoptotic Bcl-2 members Bax, Bad and activation of caspase 3 and caspase 9, but not the activation of caspase 8 or Fas were detected in the NS1-transfected cells. p53-induced Bax expression and subsequent activation of caspase 9 is probably the apoptotic pathway in NS1-transfected cells since activation of the caspase 9 was suppressed by the p53 inhibitor and apoptosis was significantly inhibited by the caspase 9 inhibitor. Our results suggest that the cell death of the NS1-transfected cells is associated with mitochondria related apoptosis. These findings might provide alternative information for further study and characterization of B19 NS1 protein in B19 non-permissive cells.
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PMID:Human parvovirus B19 non-structural protein (NS1) induces apoptosis through mitochondria cell death pathway in COS-7 cells. 1537 Jun 68

Hepatoma is one of the most frequently occurring cancers worldwide. However, effective chemotherapeutic agents for this disease have not been developed. Acyclic retinoid, a novel synthetic retinoid, can reduce the incidence of postsurgical recurrence of hepatoma and improve the survival rate. OSI-461, a potent derivative of exisulind, can increase intracellular levels of cyclic GMP, which leads to activation of protein kinase G and induction of apoptosis in cancer cells. In the present study, we examined the combined effects of acyclic retinoid plus OSI-461 in the HepG2 human hepatoma cell line. We found that the combination of as little as 1.0 micromol/L acyclic retinoid and 0.01 micromol/L OSI-461 exerted synergistic inhibition of the growth of HepG2 cells. Combined treatment with low concentrations of these two agents also acted synergistically to induce apoptosis in HepG2 cells through induction of Bax and Apaf-1, reduction of Bcl-2 and Bcl-xL, and activation of caspase-3, -8, and -9. OSI-461 enhanced the G0-G1 arrest caused by acyclic retinoid, and the combination of these agents caused a synergistic decrease in the levels of expression of cyclin D1 protein and mRNA, inhibited cyclin D1 promoter activity, decreased the level of hyperphosphorylated forms of the Rb protein, induced increased cellular levels of the p21(CIP1) protein and mRNA, and stimulated p21(CIP1) promoter activity. Moreover, OSI-461 enhanced the ability of acyclic retinoid to induce increased cellular levels of retinoic acid receptor beta and to stimulate retinoic acid response element-chloramphenicol acetyltransferase activity. A hypothetical model involving concerted effects on p21(CIP1) and retinoic acid receptor beta expression is proposed to explain these synergistic effects. Our results suggest that the combination of acyclic retinoid plus OSI-461 might be an effective regimen for the chemoprevention and chemotherapy of human hepatoma and possibly other malignancies.
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PMID:Synergistic effects of acyclic retinoid and OSI-461 on growth inhibition and gene expression in human hepatoma cells. 1547 62

Farnesyltransferase inhibitor (FTI) acts on ras, which can ultimately enhance radiosensitivity. The objective of this study was to explore whether FTI could potentiate the antitumor efficacy of radiation in vivo, particularly in radio-resistant hepatocarcinomas (HCa-I) syngeneic to C3H/HeJ mice. The presence of ras mutations was examined by PCR and DNA sequencing. C3H/HeJ mice, bearing HCa-I, were treated with FTI, LB42907, and 25 Gy radiation. FTI was orally administered, 60 mg/kg, twice daily for 30 days. The expression of regulating molecules was analyzed by Western blotting for p53, p21(WAF1/CIP1), and the Bcl-2 family, such as Bcl-2, Bax, and Bcl-X(L/s). In HCa-I, no ras mutations were detected. Downregulation of ras by FTI was most prominent at 4 h after treatment. In a tumor growth delay assay, FTI increased the effect of the tumor's radioresponse, with an enhancement factor of 1.32. Combined irradiation and FTI increased radiation-induced apoptosis; the peak apoptotic index was 3.6% with irradiation alone and with the drug alone but 7.1% in the combined treatment group. The analysis of apoptosis-regulating molecules by Western blotting showed upregulation of p53 and p21(WAF1/CIP1) in the combined treatment group compared with those in either of the single treatment groups, but the Bcl-2 family remained unchanged. FTI, in combination with radiation therapy, may have potential benefits in cancer treatment even if there are no ras mutations. FTI could inhibit ras activity but may also affect any protein that requires farnesylation for its activity.
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PMID:Enhancement of tumor response by farnesyltransferase inhibitor in C3H/HeJ hepatocarcinoma. 1565 85

Vascular endothelial growth factor (VEGF) plays an important role in tumor angiogenesis of hepatocellular carcinoma. Inhibition of VEGF receptors could theoretically reduce angiogenesis and tumor growth in hepatocellular carcinoma, but this remains to be proven with an experimental study. This study examined the angiogenesis-dependent and angiogenesis-independent activities of PTK787/ZK222584 (PTK787), a tyrosine kinase inhibitor of VEGF receptors, in nude mice bearing human hepatocellular carcinoma xenografts. The in vitro effects of PTK787 on proliferation, apoptosis, and cell cycle distribution in human hepatocellular carcinoma cell lines were also studied. Oral administration of PTK787 resulted in a significant reduction in tumor volume and microvessel formation of hepatocellular carcinoma xenografts in nude mice. PTK787 inhibited tumor cell proliferation in a dose-dependent manner and also induced tumor cells to undergo apoptosis both in vivo and in vitro. The proapoptotic response was associated with down-regulation of Bcl-2 and Bcl-x(L) expression and induction of cleavage of caspase-3. In addition, PTK787 induced growth arrest in hepatocellular carcinoma cells, which was associated with G1 arrest and partial G2-M block. This effect correlated with an increase in p21(WAF1/ CIP1) (p21) and p27KIP1 (p27) protein expression. In conclusion, this study showed that PTK787 is a potent inhibitor of tumor growth in hepatocellular carcinoma by both antiangiogenic effect and direct effects on tumor cell proliferation and apoptosis. Our data suggest that blockage of VEGF receptors may provide an effective therapeutic approach for human hepatocellular carcinoma.
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PMID:Both antiangiogenesis- and angiogenesis-independent effects are responsible for hepatocellular carcinoma growth arrest by tyrosine kinase inhibitor PTK787/ZK222584. 1586 64


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