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)

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive lymphoproliferative disease of very poor clinical prognosis associated with infection by the human T-cell leukemia virus type I (HTLV-I). Treatment of patients with ATLL using conventional chemotherapy has limited benefit because HTLV-I cells are refractory to most apoptosis-inducing agents. In this study, we report that Celecoxib induces cell death via the intrinsic mitochondrial pathway in HTLV-I transformed leukemia cells. Treatment with Celecoxib was associated with activation of Bax, decreased expression of Mcl-1, loss of the mitochondrial membrane potential and caspase-9-dependent apoptosis. These effects were independent from Bcl-2 and Bcl-xL. We also found that Celecoxib inhibited the Akt/GSK3 beta survival pathway in HTLV-I cells.
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PMID:Celecoxib disrupts the canonical apoptotic network in HTLV-I cells through activation of Bax and inhibition of PKB/Akt. 1795 3

Cyclooxygenase-2 (COX-2), involved in the inhibition of apoptosis and, the potentiation of cell growth, is frequently overexpressed in human malignancies including osteosarcoma (OS). We have attempted to identify the anti-proliferation of celecoxib, a selective COX-2 inhibitor, and the combination of celecoxib and cisplatin in MG-63 cells, and to explore the potential molecular mechanisms involved. MG-63 cells were treated with the combination of celecoxib and cisplatin or either agent alone for 48h in serum-supplemented medium. Celecoxib caused G1 phase arrest and significantly inhibited cell growth, as well as potentiating cisplatin-induced apoptosis. The effect was dose-dependent, and apoptotic changes such as DNA fragments and apoptotic bodies were observed. However, downregulation of COX-2 did not occur in cells treated with celecoxib. Phosphoinositide-3-kinase (PI3K)/Akt, survivin, bcl-2 were significantly downregulated in cells treated with the combination of celecoxib and cisplatin, and decreased survivin and bcl-2 levels were found in cells with wortmannin, a specific PI3K inhibitor. Moreover, the decreased expressions of procaspase-9, procaspase-3 and cleaved PARP-1 were detected by Western blot analysis. Therefore, celecoxib exerts its anti-tumor activities through COX-2-independent mechanisms, which may be PI3K/Akt-dependent, and survivin and bcl-2-related. PI3K may be at the center of the celecoxib effects, which play an essential role in the regulation of survivin and Bcl-2.
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PMID:Celecoxib, a cyclooxygenase-2 inhibitor, induces apoptosis in human osteosarcoma cell line MG-63 via down-regulation of PI3K/Akt. 1807 66

Cyclooxygenase (COX)-2 has emerged as an exciting target for therapeutic intervention in the management of cancer. Immunohistochemistry studies have indicated higher expression of COX-2 in cancerous versus benign prostatic tissue. We have explored the role of COX-2 in prostate cancer in terms of attenuation of apoptosis and sensitivity to pharmacological agents, including COX-2 inhibitors. The human prostate cancer cell line LNCaP was stably transfected with COX-2 (LNCaPCOX-2) and compared with the empty vector control line (LNCaPneo). Chemosensitivity testing indicated no change in sensitivity to the cytotoxic effects of COX-2 inhibitors celecoxib or sulindac or VP16. However, LNCaPCOX-2 cells showed 3-fold resistance to carboplatin, which was partially reversed by coincubation with the phosphatidylinositol 3-kinase inhibitor wortmannin. Concomitant with reduced apoptotic response to cytotoxic agents, LNCaPCOX-2 cells expressed increased levels of survivin and Bcl-2 with enhanced activation of AKT. We also investigated the effects of celecoxib on expression levels of genes relevant to prostate cancer and drug resistance in our model system using quantitative polymerase chain reaction analysis. Celecoxib treatment resulted in highly significant increases in the mRNA expression of the smooth muscle component desmin, the detoxification enzyme glutathione S-transferase pi (GSTpi), and nonsteroidal anti-inflammatory response gene (NAG-1) in the LNCaPCOX-2 cell line compared with LNCaPneo cells. Significant decreases in survivin levels and increases in GSTpi and NAG-1 appeared to be COX-2-dependent effects because they were more pronounced in LNCaPCOX-2 cells. Our findings indicate both COX-2-dependent and -independent mechanisms attributable to celecoxib and support its utility in the management of prostate cancer.
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PMID:The effects of cyclooxygenase-2 expression in prostate cancer cells: modulation of response to cytotoxic agents. 1808 46

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.
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PMID:Importance of Bak for celecoxib-induced apoptosis. 1877 87

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.
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PMID:Anticancer effect of celecoxib via COX-2 dependent and independent mechanisms in human gastric cancers cells. 1892 1

This study was designed to evaluate the effect of long-term pretreatment with celecoxib, a cyclooxygenase-2 inhibitor, on myocardial infarct size. Celecoxib (3 mg/kg/day i.p; n = 16) or vehicle (DMSO 50%; EtOH 15%; distilled water, n = 16) was administered chronically to male Sprague-Dawley rats through ALZET osmotic pumps for 28 days. Under anaesthesia, the animals were then subjected to left anterior descending coronary artery occlusion for 40 minutes, followed by 24-hour reperfusion. The results show that myocardial infarct size in celecoxib-treated rats was significantly reduced compared to the control group (37.5 +/- 2.5% versus 48.0 +/- 2.6% of the area at risk, P < 0.05, n = 10 per group). Accumulation of neutrophils, estimated by myeloperoxidase levels, indicated an increase in the ischemic area without any significant difference between groups. No significant difference was observed between the treated and vehicle groups in terms of plasma prostaglandin E2 and tumour necrosis factor-alpha. Apoptosis, evaluated by Bax/Bcl-2 and terminal dUTP nick-end labelled-positive cells, was significantly decreased in the subendocardial layer of the ischemic area in celecoxib-treated rats. This study indicates that pretreatment with celecoxib can reduce infarct size by a mechanism, which may involve apoptosis inhibition.
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PMID:Chronic pretreatment with celecoxib reduces infarct size. 1952 17

The cyclooxygenase-2 inhibitor Celecoxib is a potent inducer of apoptosis in tumor cells. In most cellular systems Celecoxib induces apoptosis via an intrinsic, mitochondrial apoptosis pathway. We recently showed that in Bax-negative Jurkat cells expression of pro-apoptotic Bak is essential for Celecoxib-induced mitochondrial damage and apoptosis induction. Aim of the present study was to identify specific pro- and anti-apoptotic members of the Bcl-2 family involved in the regulation of Bak activation, and subsequent apoptosis upon treatment with Celecoxib in the Jurkat cell model. Our results show that apoptosis in response to Celecoxib required the presence of Noxa and downregulation of the anti-apoptotic protein Mcl-1. Celecoxib-induced Bak activation and subsequent apoptosis could be inhibited by overexpression of Bcl-xL but not by the very similar Bcl-2. In Bcl-xL-overexpressing cells neutralization of both, Mcl-1 and Bcl-xL, was prerequisite for an efficient induction of apoptosis. Our data reveal an important role of the Mcl-1/Noxa axis for Celecoxib-induced apoptosis and suggest that Celecoxib may be of value for treatment of tumors addicted to Mcl-1 and for combined treatment approaches targeting anti-apoptotic Bcl-2 family members.
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PMID:Differential effects of anti-apoptotic Bcl-2 family members Mcl-1, Bcl-2, and Bcl-xL on celecoxib-induced apoptosis. 1966 51

Cyclooxygenase (COX)-2 is overexpressed in many human tumors including neuroblastoma (NB) and promotes tumor progression. We evaluated the antitumor effect of irinotecan (CPT-11) treatment combined with prolonged very low-dose administration of celecoxib, a selective COX-2 inhibitor, against three human NB xenografts, TNB9, TS-N-2nu, and TS-N-5nu. In addition, the effects of the celecoxib-combined treatment were examined on tumor cell proliferation, apoptosis, angiogenesis, and expression of vascular endothelial growth factor and apoptosis-related proteins in xenografts. Celecoxib administered daily at 5 mg/kg body weight/day could not prevent the growth of any of the NB xenografts. However, the combination of daily low-dose CPT-11 (5.9 mg/kg body weight/day) and simultaneous very low-dose celecoxib resulted in highly significant suppression of tumor growth in all three xenografts (P < 0.001) compared not only with low-dose CPT-11 therapy alone but also with the combination therapy of intermittent conventional-dose CPT-11 (59 mg/kg body weight) and celecoxib accompanied by decreased proliferation and increased induction of apoptosis in tumor cells. Induction of apoptosis by CPT-11 with and without celecoxib was associated with the up-regulation of Bax expression and the down-regulation of Bcl-2 expression. The enhanced antitumor effect of the combination of the two drugs against the NB xenografts might be partially COX-2-independent and was probably mediated through multiple factors including diminished expression of VEGF and activation of the caspase-dependent mitochondrial apoptosis pathway. These findings demonstrate that prolonged low-dose CPT-11 treatment combined with very low-dose celecoxib shows promising antitumor activity through the blockage of multiple critical targets related to NB tumor cell survival and proliferation.
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PMID:Prolonged low-dose administration of the cyclooxygenase-2 inhibitor celecoxib enhances the antitumor activity of irinotecan against neuroblastoma xenografts. 1967 86

The aim of the study is to determine the effect of Celecoxib administration, dietary or topical, on expression of Ki-67, c-erb-B2, bcl-2 and bax genes in rat tongue by the immunohistochemistry methods and also tdt-mediated dupt-biotin nick end labeling assay in order to explore their role in malignant transformation and the proliferation rate, apoptosis rate in tongue squamous cell carcinoma. Effects of celecoxib on tongue carcinogenesis were investigated in 40 adult male Sprague Dawley 3-3.5 months rats initiated with 30 ppm 4-nitroquinoline-1-oxide. The immunohistochemical expression of Ki-67, bcl2, bax and c-erb-B2 were also examined for analysis of the effects of Celecoxib on tongue carcinogenesis. Differences among groups were statistically analyzed with one-way analysis of variance (SPSS-13, p < 0.05). At week 8, the incidence of tongue precancer lesions was reduced by Celecoxib and there were significant differences in the average expression of Ki-67 (p = 0.00), c-erb-B2 (p = 0.01), bax (p = 0.02), bcl2 (p = 0.02) and also in TUNEL assay (p = 0.00). The results suggest probably that the level of c-erb-B2, bcl-2 and bax expression could show behavior of squamous cell carcinoma in initiation phase of developing carcinoma.
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PMID:Effect of dietary and topical Celecoxib on expression of bcl-2, bax, c-erb-B2 and Ki67 in carcinogen-induced tongue carcinoma in rat. 1980 4

Theobroma cacao L. is known to have potential cardiovascular and cancer chemopreventive activities because of its high content of phenolic phytochemicals and their antioxidant capacities. In this work, we show for the first time that cocoa inhibits drug-triggered liver cytotoxicity by inducing autophagy. Phenolic-rich extracts of both unroasted and roasted cocoa prevented Celecoxib-induced cell viability inhibition in MLP29 liver cells because of the accumulation of G1 cells and cell death. Death prevented by cocoa had hallmarks of apoptosis such as the sub-G1 peak at flow cytometry and activation of Bax expression, together with down-regulation of Bcl-2, released cytochrome c in the cytosol with activation of Caspase 3, indicating that components of the apoptotic pathway such as Bax or upstream are major targets of cocoa phytochemicals. The protective effect of cocoa against liver cytotoxicity by Celecoxib was probably accounted for by inducing the autophagic process, as shown by enhanced Beclin 1 expression and accumulation of monodansylcadaverine in autolysosomes. This fact suggests that apoptosis was prevented by inducing autophagy. Finally, considering all these findings, we suggest that cocoa can be added to the list of natural chemopreventive agents whose potential in hepatopathy prevention and therapy should be evaluated.
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PMID:Protective activity of Theobroma cacao L. phenolic extract on AML12 and MLP29 liver cells by preventing apoptosis and inducing autophagy. 1988 72


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