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)

Thymoquinone (TQ), derived from the medicinal plant Nigella sativa, exhibits antiinflammatory and anticancer activities through mechanism(s) that is not fully understood. Because numerous effects modulated by TQ can be linked to interference with the nuclear factor-kappaB (NF-kappa B) signaling, we investigated in detail the effect of this quinone on NF-kappa B pathway. As examined by DNA binding, we found that TQ suppressed tumor necrosis factor-induced NF-kappa B activation in a dose- and time-dependent manner and inhibited NF-kappaB activation induced by various carcinogens and inflammatory stimuli. The suppression of NF-kappaB activation correlated with sequential inhibition of the activation of I kappa B alpha kinase, I kappa B alpha phosphorylation, I kappa B alpha degradation, p65 phosphorylation, p65 nuclear translocation, and the NF-kappa B-dependent reporter gene expression. TQ specifically suppressed the direct binding of nuclear p65 and recombinant p65 to the DNA, and this binding was reversed by DTT. However, TQ did not inhibit p65 binding to DNA when cells were transfected with the p65 plasmid containing cysteine residue 38 mutated to serine. TQ also down-regulated the expression of NF-kappa B-regulated antiapoptotic (IAP1, IAP2, XIAP Bcl-2, Bcl-xL, and survivin), proliferative (cyclin D1, cyclooxygenase-2, and c-Myc), and angiogenic (matrix metalloproteinase-9 and vascular endothelial growth factor) gene products. This led to potentiation of apoptosis induced by tumor necrosis factor and chemotherapeutic agents. Overall, our results indicate that the anticancer and antiinflammatory activities previously assigned to TQ may be mediated in part through the suppression of the NF-kappa B activation pathway, as shown here, and thus may have potential in treatment of myeloid leukemia and other cancers.
 ...
PMID:Targeting nuclear factor-kappa B activation pathway by thymoquinone: role in suppression of antiapoptotic gene products and enhancement of apoptosis. 3018 Dec 5

Cyclooxygenase-2 (COX-2), one isoform of cyclooxygenase proinflammatary enzymes, is a causal factor for tumor development, invasion, metastasis, and chemoresistance. It is frequently overexpressed in a variety of human malignancies, including laryngeal carcinoma. To investigate its possibility as a therapeutic target for the treatment of laryngeal carcinoma, we employed RNA interference technology to downregulate endogenous gene COX-2 expression in laryngeal carcinoma cells and analyzed its phenotypical changes. Results showed that shRNA-mediated downregulation of COX-2 expression in human laryngeal carcinoma cells significantly inhibited cell proliferation and colony formation in vitro and reduced the potential of tumorigenicity in vivo. The specific downregulation led to cell arrest in the G(0)/G(1) phase of cell cycle and final apoptosis induction. The increased apoptosis was associated with the ratios of Bcl-2 or Bcl-xL/Bax. In the present study, we also observed that the downregulation of COX-2 could obviously enhanced the cytotoxic effect of Taxanes both in vitro and in vivo. All these results suggest that knockdown of COX-2 expression can lead to potent antitumor activity and chemosensitizing activity to taxanes in human laryngeal carcinomas.
 ...
PMID:shRNA-targeted cyclooxygenase (COX)-2 inhibits proliferation, reduces invasion and enhances chemosensitivity in laryngeal carcinoma cells. 1859 38

The selective cyclooxygenase-2 (COX-2) inhibitor celecoxib constitutes the prototype of pro-apoptotic agents acting through the intrinsic death pathway in a Bcl-2 independent manner. To gain further insight into celecoxib-mediated apoptosis regulation at the level of the mitochondria we tested in how far the crucial pro-apoptotic Bcl-2 proteins Bak and Bax were involved using clones of the Bax-deficient Jurkat T-lymphoma cell model either expressing Bak (Jurkat Bak positive) or being negative for Bak (Jurkat Bak negative), or overexpressing Bcl-2 (Jurkat Bcl-2). Celecoxib induced substantial apoptosis in Jurkat Bak-positive cells. Overexpression of Bcl-2 had only limited protective effects. However, loss of Bak-expression conferred almost complete resistance of Jurkat cells to celecoxib-induced apoptosis. Neither enhanced celecoxib-concentrations nor prolonged incubation times were sufficient to normalize apoptotic rates upon celecoxib-treatment in these Bak/Bax-negative cells. In line with that observation, siRNA-mediated silencing of Bak in the Bak-positive Jurkat cells largely reduced the extent of celecoxib-induced cell death. Interestingly, in celecoxib-sensitive Bak-positive cells, celecoxib-treatment resulted in down-regulation of the anti-apoptotic Bcl-2 protein Mcl-1 which may contribute to celecoxib-mediated activation of Bak-dependent apoptosis. Taken together our data clearly show for the first time the functional relevance of Bak for celecoxib-induced apoptosis in Bax-deficient Jurkat T-lymphoma cells.
 ...
PMID:Importance of Bak for celecoxib-induced apoptosis. 1877 87

Compounds isolated from members of the Zingiberaceae family are traditionally used as a medicine against inflammatory diseases, but little is known about the mechanism. Here, we report the isolation and structural identification of coronarin D [E-labda-8(17),12-diene-15-ol], a labdane-type diterpene, from Hedychium coronarium and delineate its mechanism of action. Because the transcription factor nuclear factor-kappaB (NF-kappaB) is a key mediator of inflammation, apoptosis, invasion, and osteoclastogenesis, we investigated the effect of coronarin D on NF-kappaB activation pathway, NF-kappaB-regulated gene products, and NF-kappaB-regulated cellular responses. The coronarin D inhibited NF-kappaB activation induced by different inflammatory stimuli and carcinogens. This labdane also suppressed constitutive NF-kappaB activity in different cell lines and inhibited IkappaBalpha kinase activation, thus leading to the suppression of IkappaBalpha phosphorylation, degradation, p65 nuclear translocation, and reporter gene transcription. Coronarin D also inhibited the NF-kappaB-regulated gene products involved in cell survival (inhibitor of apoptosis protein 1, Bcl-2, survivin, and tumor necrosis factor receptor-associated factor-2), proliferation (c-myc, cyclin D1, and cyclooxygenase-2), invasion (matrix metalloproteinase-9), and angiogenesis (vascular endothelial growth factor). Suppression of these gene products by the diterpene enhanced apoptosis induced by TNF and chemotherapeutic agents, suppressed TNF-induced cellular invasion, and abrogated receptor activator of NF-kappaB ligand-induced osteoclastogenesis. Coronarin D was found to be more potent than its analogue coronarin D acid. Overall, our results show that coronarin D inhibited NF-kappaB activation pathway, which leads to inhibition of inflammation, invasion, and osteoclastogenesis, as well as potentiation of apoptosis.
 ...
PMID:Coronarin D, a labdane diterpene, inhibits both constitutive and inducible nuclear factor-kappa B pathway activation, leading to potentiation of apoptosis, inhibition of invasion, and suppression of osteoclastogenesis. 3018 34

Cyclooxygenase-2 (COX-2) inhibitors cause growth inhibition of human gastric carcinoma cells, but it remains unclear whether this is both COX-2 dependent and independent. The related mechanisms remain to be determined. Both low COX-2 expressing gastric carcinoma and high COX-2 expressing gastric carcinoma cells were used to study the effect and mechanisms of celecoxib on gastric carcinoma cell growth. Celecoxib resulted in comparable growth inhibition in AGS cells with stable transfections of small interfering RNA (siRNA) against COX-2 (SAC) and negative control vector (NC) cells. Simultaneously, celecoxib resulted in significant reduction of Bcl-2 and significant increase of p21(WAF1) and p27(KIP1) in SAC and NC cells. The present study shows that celecoxib causes growth inhibition of gastric carcinoma cells by decreasing Bcl-2 of cyclooxygenase-2-dependent pathway, and by increasing p21(WAF1) and p27(KIP1) of cyclooxygenase-2-independent pathway. These data extend our knowledge on the effect and mechanisms of celecoxib-induced inhibition of gastric carcinoma cell growth.
 ...
PMID:Anticancer effect of celecoxib via COX-2 dependent and independent mechanisms in human gastric cancers cells. 1892 1

Picroliv, an iridoid glycoside derived from the plant Picrorhiza kurroa, is used traditionally to treat fever, asthma, hepatitis, and other inflammatory conditions. However, the exact mechanism of its therapeutic action is still unknown. Because nuclear factor-kappaB (NF-kappaB) activation plays a major role in inflammation and carcinogenesis, we postulated that picroliv must interfere with this pathway by inhibiting the activation of NF-kappaB-mediated signal cascade. Electrophoretic mobility shift assay showed that pretreatment with picroliv abrogated tumor necrosis factor (TNF)-induced activation of NF-kappaB. The glycoside also inhibited NF-kappaB activated by carcinogenic and inflammatory agents, such as cigarette smoke condensate, phorbol 12-myristate 13-acetate, okadaic acid, hydrogen peroxide, lipopolysaccharide, and epidermal growth factor. When examined for the mechanism of action, we found that picroliv inhibited activation of IkappaBalpha kinase, leading to inhibition of phosphorylation and degradation of IkappaBalpha. It also inhibited phosphorylation and nuclear translocation of p65. Further studies revealed that picroliv directly inhibits the binding of p65 to DNA, which was reversed by the treatment with reducing agents, suggesting a role for a cysteine residue in interaction with picroliv. Mutation of Cys(38) in p65 to serine abolished this effect of picroliv. NF-kappaB inhibition by picroliv leads to suppression of NF-kappaB-regulated proteins, including those linked with cell survival (inhibitor of apoptosis protein 1, Bcl-2, Bcl-xL, survivin, and TNF receptor-associated factor 2), proliferation (cyclin D1 and cyclooxygenase-2), angiogenesis (vascular endothelial growth factor), and invasion (intercellular adhesion molecule-1 and matrix metalloproteinase-9). Suppression of these proteins enhanced apoptosis induced by TNF. Overall, our results show that picroliv inhibits the NF-kappaB activation pathway, which may explain its anti-inflammatory and anticarcinogenic effects.
 ...
PMID:Modification of cysteine residue in p65 subunit of nuclear factor-kappaB (NF-kappaB) by picroliv suppresses NF-kappaB-regulated gene products and potentiates apoptosis. 3018 11

Although inhibition of cyclooxygenase-2 (COX-2) or activation of peroxisome proliferators-activated receptor gamma (PPAR-gamma) leads to growth inhibition in malignancies, the synergistic anti-tumor effects of combination of COX-2 inhibitor (NS-398) and PPAR-gamma agonist (rosiglitazone) on the human pancreatic cancer cells remains unknown. Here, we evaluated the effects of NS-398 and/or rosiglitazone on the cell proliferation and apoptosis in a pancreatic cancer cell line, SW1990. NS-398 and rosiglitazone decreased cell proliferation in a dose- and time-dependent manner. Proliferating cell nuclear antigen (PCNA) labeling index significantly decreased in the cells treated with either NS-398 or rosiglitazone. Both NS-398 and rosiglitazone alone induced apoptotic cell death of SW1990. The combination of NS-398 and rosiglitazone exerted synergistic effects on proliferation inhibition, and apoptosis induction in SW1990 cells, with down-regulation of Bcl-2 and up-regulation of Bax expression. Our results indicate that simultaneous targeting of COX-2 and PPAR-gamma inhibits pancreatic cancer development more effectively than targeting each molecule alone.
 ...
PMID:Inhibition of COX-2 and activation of peroxisome proliferator-activated receptor gamma synergistically inhibits proliferation and induces apoptosis of human pancreatic carcinoma cells. 1905 68

We report mechanism-based evidence for the anticancer efficacy of a protein fraction, SF2 (Sesbania fraction 2) isolated from the flower of the medicinal plant, Sesbania grandiflora (S. grandiflora). The fraction was evaluated in two murine ascites tumour cell lines and human cancer cell lines of different origin for its anticancer effect. SF2 inhibited cell proliferation and induced apoptosis as demonstrated by DNA fragmentation and externalization of phosphatidyl serine in Daltons lymphoma ascites (DLA) and colon cancer cells (SW-480). Sensitivity to SF2 in these cells was associated with activation of caspases 3, 8 and 9, poly (ADP-ribose) polymerase cleavage and cytochrome C release which attests apoptosis induced cell death. Mechanistically, SF2 down-regulated phorbol myristate acetate (PMA) induced NF-kappaB, a transcription factor which controls the expression of genes encoding proteins involved in cell regulation and growth control. Additionally, SF2 also down-regulated anti-apoptotic factors such as Bcl-2, p-Akt and cyclooxygenase-2 induced by the tumour promoter PMA suggestive of a possible explanation for its anticancer effect. In vivo studies using ascites and solid tumour models strongly support in vitro findings as SF2 administration increased the life span and decreased the tumour volume in mice bearing tumour. In vivo toxicological evaluation revealed the pharmacological safety of SF2 and may serve as a potential anticancer drug candidate.
 ...
PMID:A novel protein fraction from Sesbania grandiflora shows potential anticancer and chemopreventive efficacy, in vitro and in vivo. 1918 44

Several diseases are characterized by chronic inflammation, a condition frequently associated with angiogenesis and fibrogenesis that account for the development of granulation tissue. Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) is a crucial modulator of intracellular prosurvival signaling pathways and is implicated in the pathogenesis of inflammatory process. In this study, we have investigated the role of NF-kappaB in the angiogenic and fibrogenic response induced by lambda-carrageenin in a rat model of chronic inflammation at 1, 3, and 5 days. The subcutaneous implant of lambda-carrageenin-soaked sponges in rat induced a time-related increase of granulation tissue formation accompanied by intense neovascularization. These lambda-carrageenin-induced changes were significantly reduced by coinjection of wild-type oligodeoxynucleotide (WT ODN) decoy to NF-kappaB. Molecular, morphological, and ultrastructural analysis performed on whole granulation tissue demonstrated: (1) inhibition of NF-kappaB/DNA binding activity; (2) downregulation of cyclooxygenase-2, matrix metalloproteinase-9, tumor necrosis factor-alpha, and vascular endothelial growth factor; (3) upregulation of thrombospondin (TSP)-1 at 1 day and TSP-2 at 5 days; and (4) increase in Bax to Bcl-2 ratio. Our findings show that the blockade of NF-kappaB activation by WT ODN decoy prevents the development of granulation tissue induced by lambda-carrageenin-soaked sponge implant upregulating Bax as well as TSP-1 and TSP-2 expression.
 ...
PMID:NF-kappaB blockade upregulates Bax, TSP-1, and TSP-2 expression in rat granulation tissue. 1918 70

Endometrial cancer is the most common gynecological malignancy in developed countries and represents the eighth leading cause of cancer related death in women. The growing incidence of endometrial cancer leads scientists and oncologists to identify effective preventive measures and also molecular markers for diagnosis and prognosis. Chemotherapy and hormone therapy is the mainstay treatment option for advanced and recurrent endometrial cancer and response to therapy is one of the most important factor which favors prognosis and overall survival. In recent years, there have been major advances in the treatment of patients with endometrial cancer. Despite advances made in the treatment of this cancer, the overall survival of patients has not significantly improved because considerable number of patients harbor tumor refractory to these therapies and the majority of the initially responsive tumors become refractory to treatments. Therefore, determination of sensitivity/resistance is becoming increasingly important for individualization of endometrial cancer therapy. The aim of this review is to present the existing knowledge about the molecular markers that could play a crucial role in determining resistance to chemo- and hormone therapy. Extensive literature search for the cell signaling pathways and factors responsible for chemoresistance have been performed and reviewed. Several recent studies suggest that deregulations in the apoptotic pathways (such as p53, Fas/FasL, Bcl-2 family proteins, inhibitor of apoptosis proteins), survival pathways (PI3K/AKT, MAPK), hormone receptor signaling pathways (progesterone receptor), Cyclooxygenase-2 and Her-2 are considered as key factors involved in the onset and maintenance of therapeutic resistance, suggesting that resistance is a multi-factorial phenomenon.
 ...
PMID:Resistance to chemotherapy and hormone therapy in endometrial cancer. 1919 80


<< Previous 1 2 3 4 5 6 7 8 9 10