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)

Numerous recent reports suggest that statins (hydroxy-3-methylglutaryl-CoA reductase inhibitors) exhibit potential to suppress tumorigenesis through a mechanism that is not fully understood. Therefore, in this article, we investigated the effects of simvastatin on TNF-alpha-induced cell signaling. We found that simvastatin potentiated the apoptosis induced by TNF-alpha as indicated by intracellular esterase activity, caspase activation, TUNEL, and annexin V staining. This effect of simvastatin correlated with down-regulation of various gene products that mediate cell proliferation (cyclin D1 and cyclooxygenase-2), cell survival (Bcl-2, Bcl-x(L), cellular FLIP, inhibitor of apoptosis protein 1, inhibitor of apoptosis protein 2, and survivin), invasion (matrix mellatoproteinase-9 and ICAM-1), and angiogenesis (vascular endothelial growth factor); all known to be regulated by the NF-kappaB. We found that simvastatin inhibited TNF-alpha-induced NF-kappaB activation, and l-mevalonate reversed the suppressive effect, indicating the role of hydroxy-3-methylglutaryl-CoA reductase. Simvastatin suppressed not only the inducible but also the constitutive NF-kappaB activation. Simvastatin inhibited TNF-alpha-induced IkappaBalpha kinase activation, which led to inhibition of IkappaBalpha phosphorylation and degradation, suppression of p65 phosphorylation, and translocation to the nucleus. NF-kappaB-dependent reporter gene expression induced by TNF-alpha, TNFR1, TNFR-associated death domain protein, TNFR-associated factor 2, TGF-beta-activated kinase 1, receptor-interacting protein, NF-kappaB-inducing kinase, and IkappaB kinase beta was abolished by simvastatin. Overall, our results provide novel insight into the role of simvastatin in potentially preventing and treating cancer through modulation of IkappaB kinase and NF-kappaB-regulated gene products.
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PMID:Simvastatin potentiates TNF-alpha-induced apoptosis through the down-regulation of NF-kappaB-dependent antiapoptotic gene products: role of IkappaBalpha kinase and TGF-beta-activated kinase-1. 1727 59

Gossypin, a flavone originally isolated from Hibiscus vitifolius, has been shown to suppress angiogenesis, inflammation, and carcinogenesis. The mechanisms of these activities, however, are unknown. Because nuclear factor-kappaB (NF-kappaB) is associated with inflammation, carcinogenesis, hyperproliferation, invasion, and angiogenesis, we hypothesized that gossypin mediates its effects through modulation of NF-kappaB activation. In the present study, we demonstrate that gossypin (and not gossypetin, an aglycone analog) inhibited NF-kappaB activation induced by inflammatory stimuli and carcinogens. Constitutive NF-kappaB activation in tumor cells was also inhibited by this flavone. Inhibition of I kappa B alpha kinase by gossypin led to the suppression of I kappa B alpha phosphorylation and degradation, p65 nuclear translocation, and NF-kappaB-regulated gene expression. This, in turn, led to the down-regulation of gene products involved in cell survival (IAP2, XIAP, Bcl-2, Bcl-xL, survivin, and antiFas-associated death domain-like interleukin-1 beta-converting enzyme-inhibitory protein), proliferation (c-myc, cyclin D1, and cyclooxygenase-2), angiogenesis (vascular endothelial growth factor), and invasion (matrix metalloprotease-9). Suppression of these gene products by gossypin enhanced apoptosis induced by tumor necrosis factor and chemotherapeutic agents, suppressed tumor necrosis factor-induced cellular invasion, abrogated receptor activator of NF-kappaB ligand-induced osteoclastogenesis, and vascular endothelial growth factor-induced migration of human umbilical vein endothelial cells. Overall, our results demonstrate that gossypin inhibits the NF-kappaB activation pathway, which may explain its role in the suppression of inflammation, carcinogenesis, and angiogenesis.
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PMID:Gossypin, a pentahydroxy glucosyl flavone, inhibits the transforming growth factor beta-activated kinase-1-mediated NF-kappaB activation pathway, leading to potentiation of apoptosis, suppression of invasion, and abrogation of osteoclastogenesis. 1733 40

The objective of this study was to investigate the fermented culture broth of Antrodia camphorata (A. camphorata) to induce apoptosis and inhibit cyclooxygenase-2 (COX-2) in estrogen-nonresponsive (MDA-MB-231) human breast cancer cells. Treatment of the highly invasive MDA-MB-231 cells with A. camphorata (40-240 microg/ml) resulted in dose and time-dependent sequences of events marked by apoptosis, as evidenced by loss of cell viability, chromatin condensation, and internucleosomal DNA fragmentation. Apoptosis in the MDA-MB-231 cells was accompanied by release of cytochrome c, activation of caspase-3, -8, and -9, and specific proteolytic cleavage of poly (ADP-ribose) polymerase (PARP). Although the A. camphorata-induced apoptosis was associated with a reduction in Bcl-2 protein levels, negligible Bax increase was observed. Furthermore, A. camphorata treatment inhibited COX-2 protein expression and prostaglandin E2 (PGE2) production in MDA-MB-231 cells. Analysis of the study data suggests that A. camphorata exerts growth inhibition on (highly invasive) estrogen-nonresponsive human breast cancer cells through apoptosis induction associated with COX-2 inhibition, and that it may possess anticancer properties potentially valuable for application in drug products.
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PMID:Inhibition of cyclooxygenase-2 and induction of apoptosis in estrogen-nonresponsive breast cancer cells by Antrodia camphorata. 1739 24

Resistance to chemotherapeutic agents is one of the distinct features of cancer cells. We evaluate the role of activated MEK-ERK signaling in Camptotecin/irinotecan (CPT-11)-induced cell death using constitutively activated MEK1-transfected normal rat intestinal epithelial cells (IEC-caMEK cells). A CPT-11-induced inhibitory concentration of 50% was determined by WST assay. Apoptosis was evaluated by DNA staining and fragmented DNA analysis. Protein expressions were analyzed by western blotting. We also examined the role of cyclooxygenase-2 in the cell systems. IEC-caMEK cells possessed survival advantages compared to control cells. Apoptosis was remarkably suppressed in IEC-caMEK cells. Western blot analysis revealed increased expression of Bcl-2, Bcl-xL, Mcl-1, and COX-2 and decreased expression of Bak in IEC-caMEK cells. The COX-2 selective inhibitor ameliorated the antiapoptotic nature of IEC-caMEK cells. MEK activation suppressed CPT-11-induced apoptosis in IEC-caMEK cells via a COX-2- dependent mechanism. Therefore, MEK-ERK signaling may contribute to the drug-resistant nature of cancer cells.
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PMID:MEK activation suppresses CPT11-induced apoptosis in rat intestinal epithelial cells through a COX-2-dependent mechanism. 1739 18

Cyclooxygenase-2 (COX-2) inhibitors have been shown to exert inhibitory effects on many types of malignant tumors and several groups have suggested that COX-2 inhibitors enhance the cytotoxic effects of other anti-cancer agents. We previously reported that meloxicam has an anti-tumorigenic effect on COX-2-expressing osteosarcoma cells. In the current study, we evaluated the synergy between meloxicam and cisplatin (CDDP), doxorubicin (DXR) and 4-hydroperoxy ifosfamide (4OOH-IFM), using the human osteosarcoma cell line, MG-63. Cytotoxicity was determined using 3-(4,5'-dimethylthiazol-2-yl)-2,5'-diphenyltetrazolium bromide (MTT) assays, and isobolographic analysis was used to evaluate any synergy. Apoptotic activity was determined by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL), and by evaluating Bax and Bcl-2 expression levels using real-time RT-PCR and western blotting analysis. Cell cycling was evaluated by flow cytometry. The cytotoxic effects of CDDP and DXR were enhanced synergistically in the presence of meloxicam and were partially due to an increase in apoptosis. By contrast, meloxicam enhanced neither the cytotoxic nor the apoptotic activity of 4OOH-IFM. Combining meloxicam with DXR significantly up-regulated Bax expression, whereas it down-regulated Bcl-2 expression in combination with CDDP. Furthermore, the number of cells in the G2/M phase was significantly increased in DXR-treated samples by the addition of meloxicam, but not in CDDP-treated or 4OOH-IFM-treated samples. These results suggest a potential clinical application of meloxicam in combination with cytotoxic drugs in patients with COX-2-positive osteosarcoma.
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PMID:Synergistic effects of meloxicam and conventional cytotoxic drugs in human MG-63 osteosarcoma cells. 1739 21

Shikonin has been reported to induce apoptosis and inhibit angiogenesis in vivo and in vitro. 6-(1-propoxyiminoalkyl)-5,8-dimethoxyoxy 1,4-naphtoquinone S-64 (DMNQ S-64) was synthesized as a shikonin derivative. In this article, the underlying apoptotic mechanism of DMNQ S-64 was examined. DMNQ S-64 exerted cytotoxicity against A549 lung carcinoma cells with IC(50) of 27.3 microM. Apoptotic bodies were observed in DMNQ S-64-treated A549 cells by 4'-6-diamidino-2-phenylindole (DAPI) staining assay. DMNQ S-64 also increased sub-G1 DNA portion in a concentration-dependent manner by flow cytometric analysis. Western blotting has revealed that DMNQ S-64 effectively activates the expression of caspase 8, 9, and 3, cleaves poly (ADP-ribose) polymerase, and increases the ratio of Bax/Bcl-2. Furthermore, cytochrome c was released in a concentration-dependent manner by DMNQ S-64. Similarly, DMNQ S-64 significantly increased caspase 3 activity by enzyme-linked immunosorbent assay (ELISA). It also significantly inhibited the level of prostaglandin E2 (PGE(2)) by ELISA and downregulated the expression of cyclooxygenase-2 (COX-2) in a concentration-dependent manner. Taken together, DMNQ S-64 may exhibit cytotoxicity against A549 cells via caspase activation and COX-2 inhibition.
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PMID:DMNQ S-64 induces apoptosis via caspase activation and cyclooxygenase-2 inhibition in human nonsmall lung cancer cells. 1740 12

Extracts of Artemisia plants possess anti-inflammatory and antioxidative activities. Eupatilin (5,7-dihydroxy-3',4',6-tri-methoxy-flavone), a pharmacologically active flavone derived from Artemisia asiatica, was shown to inhibit phorbol ester-induced cyclooxygenase-2 expression and NF-kappaB activation in mouse skin, and also to induce cell cycle arrest in ras-transformed human mammary epithelial (MCF10A-ras) cells. In this article, we examined the ability of jaceosidin (4',5,7-trihydroxy-3',6-dimethoxyflavone) isolated from Artemisia argyi to inhibit the proliferation of MCF10A-ras cells. Jaceosidin reduced the viability of MCF10A-ras cells to a greater extent than eupatilin. Jaceosidin treatment resulted in increased intracellular accumulation of reactive oxygen species (ROS) in MCF10A-ras cells, which was blocked by the antioxidant N-acetylcysteine (NAC). NAC attenuated jaceosidin-induced cytotoxicity. To better assess the proapoptotic effects of jaceosidin, we analyzed the treated cells by the flow cytometry. MCF10A-ras cells treated with jaceosidin (100 microM) exhibited the increased proportion of hypodiploid or apoptotic cells (48.72% as composed to 7.78% in control cells). Jaceosidin treatment also increased the ratio of proapoptotic Bax to the antiapoptotic Bcl-2 and induced the cleavage of caspase-3 and poly(ADP-ribose)polymerase (PARP). Moreover, jaceosidin elevated the expression of p53 and p21, while the compound inhibited the activation of ERK1/2 that is an important component of cell survival signaling.
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PMID:Jaceosidin induces apoptosis in ras-transformed human breast epithelial cells through generation of reactive oxygen species. 1740 61

Gemcitabine is currently the best treatment available for pancreatic cancer, but the disease develops resistance to the drug over time. Agents that can either enhance the effects of gemcitabine or overcome chemoresistance to the drug are needed for the treatment of pancreatic cancer. Curcumin, a component of turmeric (Curcuma longa), is one such agent that has been shown to suppress the transcription factor nuclear factor-kappaB (NF-kappaB), which is implicated in proliferation, survival, angiogenesis, and chemoresistance. In this study, we investigated whether curcumin can sensitize pancreatic cancer to gemcitabine in vitro and in vivo. In vitro, curcumin inhibited the proliferation of various pancreatic cancer cell lines, potentiated the apoptosis induced by gemcitabine, and inhibited constitutive NF-kappaB activation in the cells. In vivo, tumors from nude mice injected with pancreatic cancer cells and treated with a combination of curcumin and gemcitabine showed significant reductions in volume (P = 0.008 versus control; P = 0.036 versus gemcitabine alone), Ki-67 proliferation index (P = 0.030 versus control), NF-kappaB activation, and expression of NF-kappaB-regulated gene products (cyclin D1, c-myc, Bcl-2, Bcl-xL, cellular inhibitor of apoptosis protein-1, cyclooxygenase-2, matrix metalloproteinase, and vascular endothelial growth factor) compared with tumors from control mice treated with olive oil only. The combination treatment was also highly effective in suppressing angiogenesis as indicated by a decrease in CD31(+) microvessel density (P = 0.018 versus control). Overall, our results suggest that curcumin potentiates the antitumor effects of gemcitabine in pancreatic cancer by suppressing proliferation, angiogenesis, NF-kappaB, and NF-kappaB-regulated gene products.
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PMID:Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-kappaB-regulated gene products. 1744 Jan

In several neoplastic diseases, including hepatocellular carcinoma, the expression of P-glycoprotein and cyclooxygenase-2 (COX-2) are often increased and involved in drug resistance and poor prognosis. P-glycoprotein, in addition to drug resistance, blocks cytochrome c release, preventing apoptosis in tumor cells. Because COX-2 induces P-glycoprotein expression, we evaluated the effect of celecoxib, a specific inhibitor of COX-2 activity, on P-glycoprotein-mediated resistance to apoptosis in cell lines expressing multidrug resistant (MDR) phenotype. Experiments were done using MDR-positive and parental cell lines at basal conditions and after exposure to 10 or 50 micromol/L celecoxib. We found that 10 micromol/L celecoxib reduced P-glycoprotein, Bcl-x(L), and Bcl-2 expression, and induced translocation of Bax from cytosol to mitochondria and cytochrome c release into cytosol in MDR-positive hepatocellular carcinoma cells. This causes the activation of caspase-3 and increases the number of cells going into apoptosis. No effect was shown on parental drug-sensitive or on MDR-positive hepatocellular carcinoma cells after transfection with MDR1 small interfering RNA. Interestingly, although inhibiting COX-2 activity, 50 micromol/L celecoxib weakly increased the expression of COX-2 and P-glycoprotein and did not alter Bcl-x(L) and Bcl-2 expression. In conclusion, these results show that relatively low concentrations of celecoxib induce cell apoptosis in MDR cell lines. This effect is mediated by P-glycoprotein and suggests that the efficacy of celecoxib in the treatment of different types of cancer may depend on celecoxib concentration and P-glycoprotein expression.
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PMID:P-glycoprotein mediates celecoxib-induced apoptosis in multiple drug-resistant cell lines. 1751 Apr 21

Zyflamend, a polyherbal preparation, was designed based on constituents that exhibit antiproliferative, antiinflammatory, antioxidant, antiangiogenic, and apoptotic activities through a mechanism that is not well defined. Because the nuclear factor (NF)-kappaB has been shown to regulate proliferation, invasion, and metastasis of tumor cells, we postulated that Zyflamend modulates the activity of NF-kappa B. To test this hypothesis, we examined the effect of this preparation on NF-kappaB and NF-kappaB-regulated gene products. We found that Zyflamend inhibited receptor activator of NF-kappa B ligand-induced osteoclastogenesis, suppressed tumor necrosis factor (TNF)-induced invasion, and potentiated the cytotoxicity induced by TNF and chemotherapeutic agents, all of which are known to require NF-kappa B activation. Zyflamend suppressed NF-kappa B activation induced by both TNF and cigarette smoke condensate. The expression of NF-kappa B-regulated gene products involved in antiapoptosis (inhibitor-of-apoptosis protein 1/2, Bcl-2, Bcl-xL, FADD-like interleukin-1betaconverting enzyme/caspase-8 inhibitory protein, TNF receptor-associated factor-1, and survivin) and angiogenesis (vascular endothelial growth factor, cyclooxygenase-2, intercellular adhesion molecule, and matrix metalloproteinase-9) was also down-regulated by Zyflamend. This correlated with potentiation of cell death induced by TNF and chemotherapeutic agents. Overall, our results indicate that Zyflamend suppresses osteoclastogenesis, inhibits invasion, and potentiates cytotoxicity through down-regulation of NF-kappa B activation and NF-kappa B-regulated gene products.
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PMID:Zyflamend, a polyherbal preparation, inhibits invasion, suppresses osteoclastogenesis, and potentiates apoptosis through down-regulation of NF-kappa B activation and NF-kappa B-regulated gene products. 1751 65


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