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

This study was designed to assess the efficacy of a new antimelanoma therapeutic strategy that relies on the use of a c-myc antisense 15-mer phosphorothioate oligodeoxynucleotide ([S]ODN), in combination with cisplatin (cis-diamminedichloroplatinum; DDP), which is currently used in the clinical management of melanoma patients. Proliferation and colony formation of melanoma cells were both inhibited by the DDP/c-myc antisense [S]ODN combination to a greater extent than that observed with either agent alone. Inhibition was most effective when DDP was followed by c-myc antisense [S]ODNs. Cell cycle flow cytometric analysis of cells exposed to the two agents either alone or in combination demonstrated that (a) c-myc antisense [S]ODNs induced an accumulation of cells in S phase and apoptosis in a fraction of the cells, detectable at day 5 after the beginning of treatment; (b) DDP induced a block in G2-M phase detectable at day 1, which was partially recovered, and apoptosis similar in extent to that induced by c-myc antisense [S]ODNs; and (c) DDP and c-myc antisense [S]ODNs together induced arrest in G2-M phase, which was maximum at day 3, i.e., delayed as compared to the block induced by DDP. The combination induced a higher percentage of apoptosis, evident at day 3 from the start of treatment, that correlated with a marked reduction in Bcl-2 expression. Mice bearing human melanoma xenografts and treated sequentially with DDP and c-myc antisense [S]ODNs showed a higher inhibition of tumor growth, reduction in the number of lung metastases, and increase in life span compared with those treated with either agent alone. Together, these data lend support to the development of anticancer therapies involving oncogene-targeted antisense ODNs and conventional antineoplastic drugs.
 ...
PMID:c-myc antisense oligodeoxynucleotides enhance the efficacy of cisplatin in melanoma chemotherapy in vitro and in nude mice. 944 6

This project was undertaken to study the survival properties of various prostate cells, including normal (NHP), BPH (benign prostate hyperplasia), primary carcinoma (PCA), and metastatic prostate cancer cells (LNCaP, PC3, and Du145), in the absence of trophic factors. Cell proliferation and cell death were quantitated by enumerating the number of live cells using MTS/PMS kit and of dead (apoptotic) cells using 4',6-diamidino-2-phenylindole dihydrochloride nuclear staining. These cells demonstrated an overall survivability in the order of BPH < NHP < LNCaP < PC3 < PCA < Du145. Upon growth factor deprivation, NHP/BPH cells rapidly underwent apoptosis, leading to a decreased number of live cells. PCA/PC3/Du145 cells, in contrast, demonstrated an initial phase of aggressive growth during which apoptosis rarely occurred, followed by a "plateau" phase in which cell loss by apoptosis was compensated by cell proliferation, followed by a later phase in which apoptosis exceeded the cell proliferation. LNCaP cells demonstrated survival characteristics between those of NHP/BPH and PCA/PC3/Du145 cells. We concluded that the increased survivability in prostate cancer cells results from enhanced cell proliferation as well as decreased apoptosis. The molecular mechanisms for evasion of apoptosis in prostate cancer cells were subsequently investigated. Quantitative Western blotting was used to examine the protein expression of P53 and P21WAF-1, Bcl-2 and Bcl-X(L) (anti-apoptotic proteins), and Bax, Bak, and Bad (proapoptotic proteins). The results revealed that, upon trophic factor withdrawal, NHP and BPH cells upregulated wild-type p53 and proapoptotic proteins Bax/Bad/Bak and down-regulated the expression of P21. Furthermore, NHP and BPH cells endogenously expressed little or no Bcl-2. In sharp contrast, prostate cancer cells expressed nonfunctional P53 and various amounts of Bcl-2 proteins. Upon deprivation, these cancer cells up-regulated P21 and Bcl-2 and/or BclX(L), lost response to withdrawal-induced up-regulation of Bax/Bad/Bak or decreased or even completely lost Bax expression and expressed some novel proteins such as P25 and P54/55 complex. These data together suggest that prostate cancer cells may use multiple molecular mechanisms to evade apoptosis, which, together with increased proliferation, contribute to extended survivability of prostate cancer cells in the absence trophic factors.
 ...
PMID:Extended survivability of prostate cancer cells in the absence of trophic factors: increased proliferation, evasion of apoptosis, and the role of apoptosis proteins. 969 82

The relationship between apoptosis and chemosensitivity remains complex. We tested the chemosensitivity of 45 patients with advanced breast cancer (BC) ex vivo against anthracyclines (A: doxorubicin, epirubicin), taxanes (T: paclitaxel, docetaxel), cisplatin (DDP) and CMF and any correlation with the expression of p53, Bcl-2 and apoptosis. Viable cells were processed for ex vivo ATP Tumor Chemosensitivity Assay (ATP-TCA). Immunohistochemistry was performed in corresponding tumor samples. Apoptosis prior to chemotherapy was assayed using a TUNEL Test. Of 45 BC tested, 18 (40%) were p53+ and 37 (82%) showed high Bcl-2 expression. Apoptosis was detected in 29 (64.4%) specimens. The Ex vivo Response Rate (EVRR) for T was 75.6% in all cases. This was the highest rate among the 4 drugs tested followed by CMF (66.7%). For A and DDP the positive rates were lower (27.6% and 10.6%, respectively). A significant correlation (r = 0.589, p < or = 0.01) was found between tumors which were sensitive to A and DDP. There was no association between chemosensitivity and apoptosis. Moreover tests for p53 and Bcl-2 did not show a correlation to ex vivo chemosensitivity. Pretreatment apoptotic parameters are unlikely to predict the individual response of breast cancer to antineoplastic agents.
 ...
PMID:Lack of correlation between P53 expression, BCL-2 expression, apoptosis and ex vivo chemosensitivity in advanced human breast cancer. 1132 70

Specific activation of apoptosis in tumor cells offers a promising approach for cancer therapy. Induction of apoptosis leads to activation of specific proteases. Two major pathways for caspase activation in mammalian cells have been described. One apoptotic pathway involves members of the tumor necrosis factor family of cytokine receptors (eg death receptor 5 (DR5)). The other pathway is controlled by the Bcl-2 family of proteins. The purpose of this study was to investigate whether increased apoptosis occurs in human glioma cells following infection with a recombinant adenoviral vector encoding the human Bax gene under the control of human vascular endothelial growth factor (VEGF) promoter element (AdVEGFBax) in combination with an anti-human DR5 monoclonal antibody (TRA-8). Specific overexpression of exogenous Bax protein induced apoptosis and cell death in glioma cell lines, through activation of both caspase-8 and -9, leading to activation of downstream caspase-3. The relative sensitivity to AdVEGFBax for the glioma cell lines was U251MG>U373MG>U87MG>D54MG. The recently characterized TRA-8 monoclonal antibody induces apoptosis of most TRAIL-sensitive tumor cells by specific binding to DR5 receptors on the cellular membrane. TRA-8 induced rapid apoptosis and cell death in glioma cells, but did not demonstrate detectable cytotoxicity of primary normal human astrocytes. The efficiency of TRA-8-induced apoptosis was variable in different glioma cell lines. The relative sensitivity to TRA-8 was U373MG>U87MG>U251MG>D54MG. The combination of TRA-8 treatment and overexpression of Bax overcame TRA-8 resistance of glioma cells in vitro. Cell viability of U251MG cells was 71.1% for TRA-8 (100 ng/ml) alone, 75.9% for AdVEGFBax (5 MOI) alone and 41.1% for their combination as measured by MTS assay. Similar enhanced apoptosis results were obtained for the other glioma cell lines. In vivo studies demonstrated that the combined treatment significantly (P<0.05) suppressed the growth of U251MG xenografts and produced 60% complete tumor regressions without recurrence. These data suggest that the combination of TRA-8 treatment with specific overexpression of Bax using AdVEGFBax may be an effective approach for the treatment of human malignant gliomas.
 ...
PMID:Enhanced apoptosis following treatment with TRA-8 anti-human DR5 monoclonal antibody and overexpression of exogenous Bax in human glioma cells. 1497 47

Apoptosis plays an important role in the regulation of bone turnover. Previously, we showed that 1,25(OH)2D3, the active form of vitamin D, may increase osteoblast survival by inhibiting apoptosis induced by serum deprivation. Human osteoblasts express the Fas receptor on their surface and its interaction with Fas ligand has been closely associated with human osteoblast apoptosis. To investigate the mechanism of 1,25(OH)2D3 inhibition of apoptosis in osteoblasts isolated from human calvaria, cells were exposed to Fas antibody. Visualization of apoptotic cells using annexin V revealed a significant decrease in apoptosis at 48 h in the presence of 1,25(OH)2D3 (14 +/- 4%, P < 0.04) compared with non-treated cells (52 +/- 4%). Furthermore, flow cytometric analysis of TUNEL-labeled osteoblasts showed a significant decrease in apoptotic cells in 1,25(OH)2D3-treated cultures (12 +/- 2%) at 48 h compared with non-treated cultures (44 +/- 3%, P < 0.04). Additionally, cells treated with 1,25(OH)2D3 survived longer as found by MTS analysis. To further explore the mechanism of 1,25(OH)2D3-mediated inhibition of apoptosis, we examined the changes in activation of death domain proteins, cleavage of caspases and mitochondrial regulators of apoptosis by Western blot analysis. A significant inhibition of caspase-8 cleavage and activity in 1,25(OH)2D3-treated cells was observed in conjunction with a decrease in the expression of the proapoptotic protein Bax with a significant increase in the expression of antiapoptotic protein Bcl-2. Furthermore, the levels of p21Cip1/WAF1, which inhibits the cleavage of caspase-8, was found to be highly induced in 1,25(OH)2D3-treated cells. In summary, these results demonstrate that the anti-apoptotic effect of 1,25(OH)2D3 in human osteoblasts after the activation of Fas-ligand is mediated by the regulation of components of both the mitochondrial and Fas-related pathways.
 ...
PMID:Vitamin D inhibits Fas ligand-induced apoptosis in human osteoblasts by regulating components of both the mitochondrial and Fas-related pathways. 1520 41

Machado-Joseph disease (MJD) is an autosomal dominant spinocerebellar degeneration characterized by a wide range of clinical manifestations. An unstable CAG trinucleotide repeat expansion in MJD gene on long arm of chromosome 14 has been identified as the pathologic mutation of MJD and apoptosis was previously shown to be responsible for the neuronal cell death of the disease. In this study, we utilized human neuronal SK-N-SH cells stably transfected with HA-tagged full-length MJD with 78 polyglutamine repeats to examine the effects of polyglutamine expansion on neuronal cell survival in the early stage of disease. Various pro-apoptotic agents were used to assess the tolerance of the mutant cells and to compare the differences between cells with and without mutant ataxin-3. Concentration- and time-dependent experiments showed that the increase in staurosporine-induced cell death was more pronounced and accelerated in cells containing expanded ataxin-3 via MTS assays. Interestingly, under basal conditions, Western blot and immunocytochemical analyses showed a significant decrease of Bcl-2 protein expression and an increase of cytochrome c in cells containing expanded ataxin-3 when compared with those of the parental cells. The same reduction of Bcl-2 was further confirmed in fibroblast cells with mutant ataxin-3. In addition, exogenous expression of Bcl-2 desensitized SK-N-SH-MJD78 cells to poly-Q toxicity. These results indicated that mitochondrial-mediated cell death plays a role in the pathogenesis of MJD. In our cellular model, full-length expanded ataxin-3 that leads to neurodegenerative disorders significantly impaired the expression of Bcl-2 protein, which may be, at least in part, responsible for the weak tolerance to polyglutamine toxicity at the early stage of disease and ultimately resulted in an increase of stress-induced cell death upon apoptotic stress.
 ...
PMID:Full-length expanded ataxin-3 enhances mitochondrial-mediated cell death and decreases Bcl-2 expression in human neuroblastoma cells. 1550 52

The effect of conjugated docosahexaenoic acid (CDHA) on the inhibition of colon cancer cell growth was examined in the colo 201 human colon cancer cell line, and the effect was compared with docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). CDHA was a more potent tumor cell growth inhibitor than DHA and EPA by colorimetric 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay (IC50 for 72 h: 31.6 microM, 46.8 microM, and 56.6 microM, respectively). CDHA inhibited cell cycle progression, due to accumulation of cells in G1 phase, which involved increased p21Cip1/Waf1 and decreased cyclin D1, cyclin E, and proliferating cell nuclear antigen expression; the p53 and cyclin A levels were unchanged. Induction of apoptosis was confirmed by the appearance of sub-G1 populations, and apoptosis cascade involved upregulation of the apoptosis-enhancing proteins (Bak and Bcl-xS) and downregulation of the apoptosis-suppressing proteins (Bcl-xL and Bcl-2). CDHA modulated cell cycle regulatory proteins and apoptosis-related proteins, similar to the effects of DHA. CDHA at a dietary dose of 1.0% significantly inhibited growth of colo 201 cells transplanted in nude mice.
 ...
PMID:Conjugated docosahexaenoic acid is a potent inducer of cell cycle arrest and apoptosis and inhibits growth of colo 201 human colon cancer cells. 1557

To explore the effects of tetra-arsenic tetra-sulfide (As(4)S(4)) in treatment of human chronic myelogenous leukemia K562 cells and its mechanism, trypan blue staining and microculture MTS assay were used to measure the effects of As(4)S(4) on growth inhibition of K562 cells; the morphologic change was determined by Wright's staining assay. The apoptosis rate and cell cycle were detected by flow cytometry; the changes of transcript and protein level were determined by real-time quantitative RT-PCR and Western blot analysis, respectively. The results indicated that As(4)S(4) had significant cytotoxicity on K562 cells. At the concentration of 0.5 micromol/L, the cell viability decreased significantly after being cultured with As(4)S(4) for 24 hours. When the concentration was lower than 0.1 micromol/L, As(4)S(4) had a little effect on K562 cells. The effect of As(4)S(4) on K562 was time- and concentration- dependent. After being cultured with As(4)S(4) at the concentration of 1.0 micromol/L for 24 to 48 hours, K562 cells displayed typical morphological changes of apoptosis. At a concentration greater than or equal to 1.0 micromol/L, As(4)S(4) could induce apoptosis significantly. After 12 hours of incubation with 1.0 micromol/L As(4)S(4), the apoptosis rate increased from (3.47 +/- 0.42)% to (6.16 +/- 0.98%). At the same time, the percentage of cells in G(1) phase decreased from (69.65 +/- 3.24)% to (50.53 +/- 2.86)%, whereas the percentage of cells in G(2)/M phase increased from (9.56 +/- 2.51)% to (12.91 +/- 2.13)%. The mRNA level of Bcl-X(L) and the protein level of pAkt were down-regulated after the inhibition of As(4)S(4), while the mRNA expression of Bcl-2, Bad and Bax had no change. Both of the transcript and protein level of bcr-abl had no change after incubation with As(4)S(4). It is concluded that As(4)S(4) can inhibit the growth of K562 cells efficiently through inducing apoptosis and cell cycle arrest. It seems that As(4)S(4) interferes with pAkt pathway and down-regulates Bcl-X(L), which may be involved in the response of K562 to this agent.
 ...
PMID:[Apoptosis mechanism in human chronic myelogenous leukemia K562 cells induced by tetra-arsenic tetra-sulfide]. 1627 37

This study was designed to reveal whether the apoptosis induced in human hepatocellular carcinoma (HCC) cell lines by 5-fluorouracil (5-FU) could be enhanced by transfecting Bcl-2 small interfering RNA (siRNA). Bcl-2 siRNA and control siRNA were transfected into cells following treatment with or without 5-FU. Suppression of Bcl-2 expression was confirmed by Western blotting; cell viability was evaluated by MTS assay, and the occurrence of apoptosis in cells was evaluated by apoptosis assay. Expression of Bcl-2 protein after transfection of 20 nM Bcl-2 siRNA was significantly lower than that of control. Incubation of all cell lines with Bcl-2 siRNA reduced cell viability 96 h after 5-FU treatment compared with all other controls: Huh-7 (P < 0.01), Huh-7 with hepatitis C replicon (P < 0.01), HepG2 (P < 0.01), HLE (P < 0.05). Moreover, the proportion of apoptosis in control siRNA, Bcl-2 siRNA, control siRNA prior to 5-FU treatment, and Bcl-2 siRNA prior to 5-FU treatment groups were (4.6 +/- 2.3)%, (7.5 +/- 0.5)%, (6.0 +/- 2.1)%, and (19.5 +/- 0.86)%, respectively. The Bcl-2 siRNA prior to 5-FU treatment group showed the strongest effect of inducing apoptosis. In conclusion, the combination Bcl-2 siRNA and 5-FU might represent a new therapeutic option for HCC.
 ...
PMID:Enhanced sensitivity of human hepatoma cells to 5-fluorouracil by small interfering RNA targeting Bcl-2. 1633 77

During apoptosis, engagement of the mitochondrial pathway involves the permeabilization of the outer mitochondrial membrane (OMM), which leads to the release of cytochrome c and other apoptogenic proteins such as Smac/DIABLO, AIF, EndoG, Omi/HtraA2 and DDP/TIMM8a. OMM permeabilization depends on activation, translocation and oligomerization of multidomain Bcl-2 family proteins such as Bax or Bak. Factors involved in Bax conformational change and the function(s) of the distinct domains controlling the addressing and the insertion of Bax into mitochondria are described in this review. We also discuss our current knowledge on Bax oligomerization and on the molecular mechanisms underlying the different models accounting for OMM permeabilization during apoptosis.
 ...
PMID:Mitochondria as the target of the pro-apoptotic protein Bax. 1683 74


1 2 3 4 5 6 7 8 9 10 Next >>