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)

Because seaweed extracts have recently been found to have antioxidant and anti-tumor activities, we analyzed a hot-water-soluble polysaccharide (PS) of the marine alga Capsosiphon fulvescens for its potential as a functional foodstuff by determining its effects on cell growth and DNA synthesis. MTS assays showed that the C. fulvescens PS (Cf-PS) significantly inhibited the proliferation of cultured human cancer cells in a dose-dependent manner. Cf-PS-treated AGS cells exhibited a marked increase in caspase-3 activation and a decrease in Bcl-2 expression. In addition, phosphorylation of insulin-like growth factor-I receptor (IGF-IR) was decreased in Cf-PS-treated AGS cells as compared to non-treated control cells, which is consistent with PI3-kinase (PI3K)/Akt activation. Cf-PS also decreased IGF-I-stimulated recruitment of p85 to IGF-IR and IRS-1. These results indicate that Cf-PS inhibits cell proliferation and induces apoptosis by inhibiting IGF-IR signaling and the PI3K/Akt pathway.
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PMID:A polysaccharide of the marine alga Capsosiphon fulvescens induces apoptosis in AGS gastric cancer cells via an IGF-IR-mediated PI3K/Akt pathway. 1734 71

The aim of this study was to investigate whether downregulation of Bcl-2 expression by small interfering RNA (siRNA) against the canine Bcl-2 gene would enhance the apoptosis and sensitivity of a canine mammary gland tumor cell line (CF33) to doxorubicin. Transfections of CF33 with siRNA were performed using cationic liposomes. Sequence-specific downregulation of Bcl-2 expression was measured by semiquantitative RT-PCR and Western blot analysis. Total viable cells were determined by MTS assay and apoptotic cell rates were determined by the immunohistochemical analysis on ssDNA. Our data showed the siRNA downregulated Bcl-2 expression which increased apotosis and also increased the sensitivity of CF33 to doxorubicin. This study indicated that downregulation of Bcl-2 expression by siRNA would be useful as a new protocol to increase the effect of doxorubicin on treatment of canine mammary gland tumors, requiring a detailed evaluation of siRNA in vivo.
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PMID:The effect of small interfering RNA (siRNA) against the Bcl-2 gene on apoptosis and chemosensitivity in a canine mammary gland tumor cell line. 1753 69

The antiapoptotic protein Bcl-2 contributes to a more chemoresistant phenotype of nonsmall cell lung cancer and therefore serves as an important target for novel anticancer strategies. Interestingly, docetaxel as a standard of care for treatment of nonsmall cell lung cancer has been shown to inactivate the Bcl-2 function by phosphorylation. We investigated the Bcl-2 expression status of nonsmall cell lung cancer cells in response to cisplatin or docetaxel and its effect on sensitizing nonsmall cell lung cancer cells by Bcl-2 downregulation employing a small interfering RNA approach. Bcl-2 expression was assessed by Western blotting and RT-PCR. Cell proliferation and apoptosis of nonsmall cell lung cancer cells were measured by an MTS-based assay and Annexin V/7-Aminoactinomycin, respectively. Combination treatment of Bcl-2 small interfering RNA with cisplatin resulted in a synergistic activity. By contrast, Bcl-2 downregulation did not sensitize nonsmall cell lung cancer cells to docetaxel. Of note, docetaxel treatment resulted in Bcl-2 phosphorylation of nonsmall cell lung cancer cells, whereas cisplatin increased the Bcl-2 overall expression and abrogated Bcl-2 phosphorylation. On the basis of our findings, a Bcl-2 silencing approach appears to be a suitable strategy for sensitizing nonsmall cell lung cancer to cisplatin, but not to docetaxel.
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PMID:Bcl-2 downregulation sensitizes nonsmall cell lung cancer cells to cisplatin, but not to docetaxel. 1758 Dec 97

Anti-apoptotic proteins Bcl-2 and Bcl-xL are overexpressed in 80% of non Hodgkin's lymphoma cells and are thought to play an important role in the resistance of lymphoma cells to current chemotherapeutic agents. Gossypol, an orally-active polyphenolic aldehyde derived from the cotton plant, has been known to have potential anti-neoplastic activity. Recently, gossypol was found to bind to the BH3 binding groove of Bcl-xL and with lesser affinity to Bcl-2. The present study was conducted to determine whether gossypol increases the sensitivity of non-Hodgkin's lymphoma cells to the actions of chemotherapeutic agents by potentiating treatment-induced apoptosis. The interactions observed between gossypol and chemotherapeutic drugs were analyzed using the median effect principle (CalcuSyn analysis). Our data showed that treatment of Ramos cells with gossypol not only induced cell arrest on the G(0)/G(1) phase, but also augmented apoptosis and growth inhibition induced by etoposide (VP-16), doxorubicin hydrochloride (ADM), vincristine (VCR), and paclitaxel (taxol). However, when gossypol was combined with cisplatin (DDP) an antagonistic effect was observed. Gossypol-induced cell cycle arrest was accompanied by decreased expression of cyclin D1 in Ramos cells. In addition, the peroxisome proliferator-activated receptor (PARP) pathway is, at least in part, involved in the gossypol-induced apoptosis when combined with VP-16. These data indicate that single-agent gossypol is effective in inhibiting growth of non-Hodgkin's lymphoma cells in vitro and combination studies with certain secondary chemotherapeutic agents further demonstrate it's synergistic cytotoxicity. These findings support future preclinical and clinical studies of gossypol in the treatment of non-Hodgkin's lymphoma.
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PMID:Synergistic cytotoxicity of Bcl-xL inhibitor, gossypol and chemotherapeutic agents in non-Hodgkin's lymphoma cells. 1834 25

Head and neck squamous cell carcinomas (HNSCC) are frequently characterized by chemotherapy and radiation resistance, and by overexpression of Bcl-XL, an antiapoptotic member of the Bcl-2 protein family. In this report we examined whether cell-permeable peptides derived from the BH3 domains of proapoptotic Bax, Bad, or Bak could be used to target Bcl-XL and/or Bcl-2 in HNSCC cells, and induce apoptotic death in these cells. To render the peptides cell permeable, Antennapedia (Ant) or polyarginine (R8) peptide transduction domains were fused to the amino termini. Fluorescence microscopy of peptide-treated HNSCC cells revealed that the BH3 peptides colocalized with mitochondria, the site of Bcl-XL and Bcl-2 expression. By contrast, a mutant peptide (BaxE BH3) which cannot bind Bcl-XL or Bcl-2 was diffusely localized throughout the cytoplasm. Treatment of three HNSCC cell lines (1483, UM-22A, UM-22B) with the wild-type BH3 peptides resulted in loss of viability and induction of apoptosis, as assessed by MTS assays and annexin V staining. In general, Ant-conjugated peptides were more potent than R8-conjugated peptides, and Bad BH3 peptide was typically more potent than Bax BH3 or Bak BH3. Treatment of purified HNSCC mitochondria with BH3 peptides resulted in robust release of cytochrome c. Thus, the relative apoptosis resistance of HNSCC cells is not due to a deficit in this step of the intrinsic, mitochondrial-mediated apoptosis pathway. We conclude that cell-permeable BH3 peptides can be used to target Bcl-XL and/or Bcl-2 in HNSCC, and targeting of these proteins may have therapeutic value in the treatment of this disease.
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PMID:Targeting antiapoptotic Bcl-2 family members with cell-permeable BH3 peptides induces apoptosis signaling and death in head and neck squamous cell carcinoma cells. 1797

Bcl-2 is overexpressed in a variety of human tumors and is involved in tumorigenesis and chemoresistance. In this study, we investigated the inhibitory effect of the hairpin Bcl-2 small interfering (si)RNA on the expression of the Bcl-2 gene in the cisplatin (DDP)-resistant human lung adenocarcinoma cell line A549/DDP, and the effect of Bcl-2 siRNA on drug sensitization in A549/DDP cells. Bcl-2 siRNA and negative siRNA plasmids were constructed and stably transfected into A549/DDP cells. Reverse transcription-polymerase chain reaction, immunofluorescence microscopy and Western blot analysis were used to detect the target gene expression. Spontaneous cell apoptosis was detected by acridine orange and ethidium bromide staining. Drug sensitivity of the cells to DDP and diallyl disulfide (DADS) was analyzed by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry. Expression levels of Bcl-2 mRNA and protein in siRNA stable transfectants were clearly reduced compared with negative siRNA transfectants and untreated cells. MTT results indicated that Bcl-2 transfectants had a higher cell inhibition rate after treatment with 0.2-200 microg/ml DDP or 50-200 microM DADS. Flow cytometry revealed increased apoptosis in Bcl-2 siRNA cells. After the addition of 20 microg/ml DDP or 100 microM DADS, siRNA targeting of the Bcl-2 gene specifically down-regulated gene expression in A549/DDP cells, increased spontaneous apoptosis, and sensitized cells to DDP and DADS.
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PMID:Bcl-2 small interfering RNA sensitizes cisplatin-resistant human lung adenocarcinoma A549/DDP cell to cisplatin and diallyl disulfide. 1798 74

The expression of growth hormone-releasing hormone (GHRH) and its receptors has been demonstrated in peripheral tissues as well as CNS. Recently, the functional splice variant SV1 of GHRH receptor was identified in various human cancers and cancer cell lines. Although antineoplastic activity of GHRH antagonists has been clearly demonstrated, the mechanism of action is incompletely understood. The objective of this study was the investigation of direct anti-proliferative effect of GHRH antagonist MZ-5-156 on HEC-1A human endometrial cancer cell line and the elucidation of underlying mechanisms. RT-PCR revealed the expression of mRNA for GHRH and SV1 of GHRH receptor in HEC-1A cells. MZ-5-156, at concentrations between 10(-7) and 10(-5) M, had a dose-dependent antiproliferative effect on HEC-1A cells, as determined by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, (MTS) assay. Hoechst 33342 staining and flow cytometric analysis indicated that MZ-5-156, at 10(-6) M, induced apoptosis in HEC-1A cells after 48 h of treatment. Western blot analysis of apoptosis-related proteins demonstrated that treatment with MZ-5-156 (10(-6) M) for 48 h significantly increased the protein levels of Fas, phospho-p53 (Ser46), p53AIP1 (p53-regulated Apoptosis-Inducing Protein 1), and caspase-8, -9, and -3, and decreased the protein level of Bcl-2. These results demonstrate that MZ-5-156 can directly inhibit the proliferation of human endometrial cancer cells, which express mRNA for GHRH and SV1 of GHRH receptor, presumably through the induction of p53-dependent apoptosis coupled with the up-regulation of Fas, phospho-p53 (Ser46), p53AIP1, and caspase-8, -9, and -3, and the down-regulation of Bcl-2.
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PMID:Cellular mechanisms of growth inhibition of human endometrial cancer cell line by an antagonist of growth hormone-releasing hormone. 1829 36

Sulforaphane (SUL) is an isothiocyanate naturally present in widely consumed vegetables, particularly in broccoli. SUL has recently been focused as a result of its inhibitory effects on tumor cell growth in vitro and in vivo. We used endothelial progenitor cells (EPCs) as an in vitro model to investigate the effect of SUL on the various steps of vasculogenesis and angiogenesis. Peripheral blood mononuclear cells from blood of normal human volunteers were plated on fibronectin-coated 100 mm dishes and incubated for 7 days. The viability of EPCs, treated with SUL at different doses, was assessed by MTS assay. Cell apoptosis was analyzed by flow cytometry. To determine the relative contributions of caspase-8 and caspase-9 pathways to SUL-induced apoptosis, the effect of caspase inhibitors was determined. The expression of apoptosis-related proteins (Bax, Bcl-2) was investigated by Western blot test. Finally, the effect of SUL on the ability of EPCs to form vascular-like structures on Matrigel was investigated. We clearly demonstrated that SUL induced the dose-dependent inhibition of EPCs' viability by induction of apoptosis. All caspases (caspase-3, -8, and -9) were activated during apoptosis induction by SUL, but the effect of caspase-9 was more prominent than that of caspase-8. Also, the expression of Bax was upregulated by SUL treatment. In addition to apoptosis induction, SUL dose-dependently inhibited the tube-like formation by EPCs on Matrigel. The present results demonstrate the antivasculogenic/antiangiogenic activity of SUL in vitro and open premise for the use of SUL as a multipotent anticancer agent that targets both cancer cells and the angiogenic endothelium.
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PMID:Sulforaphane stimulates activation of proapoptotic protein bax leading to apoptosis of endothelial progenitor cells. 1903 79

It is well recognized that nitric oxide (NO) is involved in tumor progression, including melanoma. Measurement of proliferative and metastatic capacity by MTS and Matrigel invasion assays, respectively, was done and showed that NO-treated melanoma cells exhibited a higher capacity compared with control, especially metastatic Lu1205 cells. Apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE/Ref-1) is a multifunctional protein and its role in tumor biology has attracted considerable attention. To determine whether APE/Ref-1 plays a role in mediating NO stimulation of melanoma progression, we investigated the effect of DETA/NO on levels of APE/Ref-1 and related downstream targets [activator protein-1 (AP-1)/JunD, matrix metalloproteinase-1 (MMP-1), Bcl-2, and inducible nitric oxide synthase (iNOS)] by Western blot and reverse transcription-PCR analysis. Following DETA/NO treatment, APE/Ref-1 and other downstream molecules were induced. Knockdown of APE/Ref-1 or AP-1/JunD by specific small interfering RNA markedly reversed the induction by NO stress of target proteins. These results present evidence for the existence of a functional feedback loop contributing to progression and metastasis of melanoma cells. Resveratrol has been shown to be an APE/Ref-1 inhibitor and significant decreases in AP-1/JunD, MMP-1, Bcl-2, and iNOS protein levels occurred after exposure to resveratrol. This phenolic antioxidant may be an appropriate choice for combining with other compounds that develop resistance by up-regulation of these molecules.
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PMID:Nitric oxide initiates progression of human melanoma via a feedback loop mediated by apurinic/apyrimidinic endonuclease-1/redox factor-1, which is inhibited by resveratrol. 1907 50

Lack of apoptotic cell death has been implicated in malignant transformation and resistance to anticancer therapies. The promotion of apoptosis in cancer cells could potentially lead to the regression and improved prognosis of refractory colorectal cancer. Synthetic triterpenoids have shown strong antitumorigenic activity towards diverse cancer cell types, but have not been investigated for colorectal cancer. In the present study, we tested the apoptosis-inducing activity of oleanane triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) and its C-28 methyl ester (CDDO-Me) and C-28 imidazole (CDDO-Im) derivatives in colorectal cancer cells lines. Cell growth/viability assay (MTS) demonstrated that colorectal cancer cells are highly sensitive to CDDO-Me at concentrations of 1.25 to 10 microM. The primary mode of tumor cell destruction was apoptosis as demonstrated by the cleavage of PARP-1, activation of procaspases -3, -8, and -9 and mitochondrial depolarization. Induction of apoptosis by CDDO-Me was associated with the inhibition of pro-survival Akt, NF-kappaB and mTOR signaling proteins and NF-kappaB-regulated anti-apoptotic Bcl-2, Bcl-xL, Bad and survivin. These studies provide rationale for clinical evaluation of CDDO-Me for the treatment of advanced chemotherapy refractory colorectal cancer.
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PMID:Synthetic triterpenoids inhibit growth, induce apoptosis and suppress pro-survival Akt, mTOR and NF-{kappa}B signaling proteins in colorectal cancer cells. 2039 97


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