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)

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

Increasing evidence supports the hypothesis that nutrition habits play a critical role in the incidence and growth of colorectal cancer. Among dietary factors, fish-derived n-3 polyunsaturated fatty acids (PUFAs) have gained particular interest, since epidemiological studies have shown a reduced incidence of this cancer in populations consuming high levels of fish. Also a variety of experimental studies and different clinical trials substantiated the beneficial role of n-3 PUFAs. Such an anti-neoplastic activity has been related to the regulatory effects exhibited by n-3 PUFAs on cell proliferation and apoptosis. Anti-angiogenic and anti-metastatic effects have been also reported for these fatty acids. Finally, it has been suggested that they may act as adjuvant therapeutic agents sensitizing tumors, including colon cancer, to different anti-neoplastic drugs. Several molecular mechanisms have been hypothesized to explain their anti-neoplastic action and, in particular, the modulating effect on the expression of several proteins involved in the regulation of cell cycle and apoptosis, such as Bcl-2, Bax, c-Myc seem to play a central role. Their inhibitory action has been also recently suggested for the molecular pathways driven by COX-2 and beta-catenin, known to play a major role in the development and progression of colon cancer. The aim of the present review is to analyze the anti-neoplastic effect of n-3 PUFAs towards colon cancer, and examine the molecular mechanisms involved.
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PMID:n-3 polyunsaturated fatty acids and the prevention of colorectal cancer: molecular mechanisms involved. 1822 Jul 42

Connections among specific proteins (Bax, Bcl-2, bFGF, COX-1, COX-2, E-cad, p15, p53, PCNA, TGFbeta3, TUNEL, vWF) in control of cell proliferation, apoptosis, cell adhesion, tumor vascularity and PGE2 content were evaluated in colon cancer as related to disease progression and survival. Tumor tissue and adjacent normal colon mucosa were obtained at curative resection in 22 patients. PGE2 concentrations were assessed in tumor tissue and tumor derived blood, splanchnic blood, peripheral venous blood and urine. Host inflammation was determined (CRP, ESR) in relationship to tumor differentiation and stage. Patients survived as expected according to Dukes A-D staging. Growth-related proteins correlated between tumor cells and stroma as well as between protein factors within tumor cells and tumor stroma. COX-2 predicted tumor tissue content of PGE2 (p<0.002), without reflection in tumor derived blood. Systemic inflammation was predicted by p15, TGFbeta3 and Bcl-2 in tumor tissue (p<0.001). p15 and vWF predicted reduced survival in ungrouped patients (p<0.02), while p15, PCNA, TGFbeta3 and vWF predicted reduced survival (p<0.0001) when patient grouping accounted for high tumor content of PGE2. Our results connect systemic inflammation and survival to COX-2 staining and increased PGE2 in colon cancer. Thus, it seems important to understand proximal signals behind upregulation of COX-2 and subsequent PGE2 production in certain tumor cells in colon cancer.
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PMID:Growth associated proteins in tumor cells and stroma related to disease progression of colon cancer accounting for tumor tissue PGE2 content. 1836 Jul 18

Radiotherapy is currently applied in the treatment of human cancers. We studied whether genistein would enhance the radiosensitivity and explored its precise molecular mechanism in cervical cancer cells. After co-treatment with genistein and irradiation, the viability, cell cycle analysis, and apoptosis signaling cascades were elucidated in CaSki cells. The viability was decreased by co-treatment with genistein and irradiation compared with irradiation treatment alone. Treatment with only gamma-irradiation led to cell cycle arrest at the G1 phase. On the other hand, co-treatment with genistein and gamma-irradiation caused a decrease in the G1 phase and a concomitant increase up to 56% in the number of G2 phase. In addition, cotreatment increased the expression of p53 and p21, and Cdc2- tyr-15-p, supporting the occurrence of G2/M arrest. In general, apoptosis signaling cascades were activated by the following events: release of cytochrome c, upregulation of Bax, downregulation of Bcl-2, and activation of caspase-3 and -8 in the treatment of genistein and irradiation. Apparently, co-treatment downregulated the transcripts of E6*I, E6*II, and E7. Genistein also stimulated irradiation-induced intracellular reactive oxygene, species (ROS) production, and co-treatment-induced apoptosis was inhibited by the antioxidant N-acetylcysteine, suggesting that apoptosis has occurred through the increase in ROS by genistein and gamma-irradiation in cervical cancer cells. Gamma-irradiation increased cyclooxygenase-1 (COX-2) expression, whereas the combination with genistein and gamma-irradiation almost completely prevented irradiation-induced COX-2 expression and PGE2 production. Co-treatment with genistein and gamma-irradiation inhibited proliferation through G2/M arrest and induced apoptosis via ROS modulation in the CaSki cancer cells.
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PMID:Sensitization of the apoptotic effect of gamma-irradiation in genistein-pretreated CaSki cervical cancer cells. 1838 72

Extensive research within the last decade has revealed that most chronic illnesses such as cancer, cardiovascular and pulmonary diseases, neurological diseases, diabetes, and autoimmune diseases exhibit dysregulation of multiple cell signaling pathways that have been linked to inflammation. Thus mono-targeted therapies developed for the last two decades for these diseases have proven to be unsafe, ineffective and expensive. Although fruits and vegetables are regarded to have therapeutic potential against chronic illnesses, neither their active component nor the mechanism of action is well understood. Resveratrol (trans-3, 5, 4'-trihydroxystilbene), a component of grapes, berries, peanuts and other traditional medicines, is one such polyphenol that has been shown to mediate its effects through modulation of many different pathways. This stilbene has been shown to bind to numerous cell-signaling molecules such as multi drug resistance protein, topoisomerase II, aromatase, DNA polymerase, estrogen receptors, tubulin and F1-ATPase. Resveratrol has also been shown to activate various transcription factor (e.g; NFkappaB, STAT3, HIF-1alpha, beta-catenin and PPAR-gamma), suppress the expression of antiapoptotic gene products (e.g; Bcl-2, Bcl-X(L), XIAP and survivin), inhibit protein kinases (e.g; src, PI3K, JNK, and AKT), induce antioxidant enzymes (e,g; catalase, superoxide dismutase and hemoxygenase-1), suppress the expression of inflammatory biomarkers (e.g., TNF, COX-2, iNOS, and CRP), inhibit the expression of angiogenic and metastatic gene products (e.g., MMPs, VEGF, cathepsin D, and ICAM-1), and modulate cell cycle regulatory genes (e.g., p53, Rb, PTEN, cyclins and CDKs). Numerous animal studies have demonstrated that this polyphenol holds promise against numerous age-associated diseases including cancer, diabetes, Alzheimer, cardiovascular and pulmonary diseases. In view of these studies, resveratrol's prospects for use in the clinics are rapidly accelerating. Efforts are also underway to improve its activity in vivo through structural modification and reformulation. Our review describes various targets of resveratrol and their therapeutic potential.
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PMID:Resveratrol: a multitargeted agent for age-associated chronic diseases. 1841 53

We previously reported that HS-1200, a synthetic chenodeoxycholic acid derivative, has apoptosis-inducing activity in various human cancer cells. The present study was undertaken to examine whether HS-1200 had an anticancer effect on HepG2 (wild-type p53) and Hep3B (p53 deleted) human hepatoma cells. Treatment of both cells with HS-1200 resulted in growth inhibition and induction of apoptosis as measured by MTT assay, nuclear staining, DNA fragmentation and flow cytometry analysis. The increase in apoptosis was associated with the alteration in the ratio of Bcl-2/Bax protein expression. In addition, flow cytometry analysis indicated that HS-1200 induced G1 phase arrest in both cells. When analyzing the expression of cell cycle-related proteins, we found that HS-1200 reduced the expression levels of cyclin D1, cyclin A, and Cdk2. HS-1200 treatment also caused an increase in the expression levels of p21 WAF1/CIP1 in HepG2 cells in a p53-dependent manner and in Hep3B cells in a p53-independent manner. Moreover, the expression level of p27 KIP1 was increased in both cell lines. We also observed that HS-1200 decreased the levels of cyclooxygenase (COX)-2 mRNA and protein expression. Furthermore, HS-1200 treatment markedly induced the Egr-1 expression at an early time point, and the increased expression levels of p53, p21 WAF1/CIP1, p27 KIP1, and COX-2 after treatment with HS-1200 were completely inhibited in HepG2 cells and partially inhibited in Hep3B cells by silencing of Egr-1, respectively. Taken together, these findings provide important new insights into the possible molecular mechanisms of the anticancer activity of the synthetic bile acid derivative, HS-1200, through Egr-1 regulation.
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PMID:A chenodeoxycholic derivative, HS-1200, induces apoptosis and cell cycle modulation via Egr-1 gene expression control on human hepatoma cells. 1855 81

Hypothermia is a standard method for organ protection during cardiac surgery in children. However, the mechanisms of hypothermia-induced cell protection have not yet been clearly established. Therefore, the aim of our studies was to elucidate molecular effects of clinically relevant mild and deep hypothermia on endothelial cells. The endothelium plays a pivotal role in the interaction between blood cells and actively participates in complex inflammatory events. We isolated primary human umbilical vein endothelial cells (HUVEC) and investigated cell viability, proliferation and inflammatory characteristics after TNF-alpha stimulation under mild (32 degrees C) and deep (17 degrees C) hypothermia in comparison to normothermia (37 degrees C). As a protective mechanism of endothelial cells kept under hypothermic conditions we found a significant upregulation of the antiapoptotic protein Bcl-2, resulting in the same cell viability under hypothermic conditions. Unexpectedly we demonstrated significantly higher IL-6 release after 6h of mild hypothermia. In contrast, hypothermia diminished inflammatory chemokines such as IL-8, MCP-1 and COX-2 protein expression which could lead to reduced leukocyte recruitment under hypothermia. Underlying mechanisms of this downregulation were found to be reduced ERK 1/2 phosphorylation and incomplete IkappaB-alpha degradation resulting in reduced NFkappaB-dependent proinflammatory gene expression. The upregulation of Bcl-2 protein and the higher IL-6 release after 6h of mild hypothermia are new and interesting cellular mechanisms of hypothermia in endothelial cell biology. Both factors may play a major role as cell protective mechanisms in hypothermia.
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PMID:Hypothermia downregulates inflammation but enhances IL-6 secretion by stimulated endothelial cells. 1879 Jun 95

It is generally believed that the French paradox is related to the consumption of red wine and not other varieties of wine, including white wine or champagne. Some recent studies have indicated that white wine could also be as cardioprotective as red wine. The present investigation compares the cardioprotective abilities of red wine, white wine, and their principal cardioprotective constituents. Different groups of rats were gavaged with red wine, white wine, resveratrol, tyrosol, and hydroxytyrosol. Red wine and its constituent resveratrol and white wine and its constituents tyrosol and hydroxytyrosol all showed different degrees of cardioprotection as evidenced by their abilities to improve postischemic ventricular performance, reduce myocardial infarct size and cardiomyocyte apoptosis, and reduce peroxide formation. It was discovered in this study that although each of the wines and their components increased the enzymatic activities of the mitochondrial complex (I-IV) and citrate synthase, which play very important roles in oxidative phosphorylation and ATP synthesis, some of the groups were more complex-specific in inducing the activity compared to the other groups. Cardioprotective ability was further confirmed by increased expression of phospho-Akt, Bcl-2, eNOS, iNOS, COX-1, COX-2, Trx-1, Trx-2, and HO-1. The results of this study suggest that white wine can provide cardioprotection similar to red wine if it is rich in tyrosol and hydroxytyrosol.
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PMID:Does white wine qualify for French paradox? Comparison of the cardioprotective effects of red and white wines and their constituents: resveratrol, tyrosol, and hydroxytyrosol. 2241 30

Sulforaphane (SFN) is a biologically active compound extracted from cruciferous vegetables, and possessing potent anti-cancer and anti-inflammatory activities. Here, we show that tumor necrosis factor-alpha (TNF-alpha), in combination with a sub-toxic dose of SFN, significantly triggered apoptosis in TNF-alpha-resistant leukemia cells (THP-1, HL60, U937, and K562), which was associated with caspase activity and poly (ADP-ribose)-polymerase cleavage. We also report that SFN non-specifically inhibited TNF-alpha-induced NF-kappaB activation through the inhibition of IkappaBalpha phosphorylation, IkappaBalpha degradation, and p65 nuclear translocation. This inhibition correlated with the suppression of NF-kappaB-dependent genes involved in anti-apoptosis (IAP-1, IAP-2, XIAP, Bcl-2, and Bcl-xL), cell proliferation (c-Myc, COX-2, and cyclin D1), and metastasis (VEGF and MMP-9). These effects suggest that SFN inhibits TNF-alpha-induced NF-kappaB activation through the suppression of IkappaBalpha degradation, leading to reduced expression of NF-kappaB-regulated gene products. Combined treatment with SFN and TNF-alpha was also accompanied by the generation of reactive oxygen species (ROS). Pre-treatment with N-acetyl-l-cysteine significantly attenuated the combined treatment-induced ROS generation and caspase-3-dependent apoptosis, implying the involvement of ROS in this type of cell death. In conclusion, the results of the present study indicate that SFN suppresses TNF-alpha-induced NF-kappaB activity and induces apoptosis through activation of ROS-dependent caspase-3.
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PMID:Sulforaphane suppresses TNF-alpha-mediated activation of NF-kappaB and induces apoptosis through activation of reactive oxygen species-dependent caspase-3. 1895 68

Identification of active principles and their molecular targets from traditional medicine is an enormous opportunity for modern drug development. Gum resin from Commiphora wightii (syn C. mukul) has been used for centuries in Ayurveda to treat internal tumors, obesity, liver disorders, malignant sores and ulcers, urinary complaints, intestinal worms, leucoderma (vitiligo), sinuses, edema and sudden paralytic seizures. Guggulsterone has been identified as one of the major active components of this gum resin. This steroid has been shown to bind to the farnesoid X receptor and modulate expression of proteins with antiapoptotic (IAP1, XIAP, Bfl-1/A1, Bcl-2, cFLIP, survivin), cell survival, cell proliferation (cyclin D1, c-Myc), angiogenic, and metastatic (MMP-9, COX-2, VEGF) activities in tumor cells. Guggulsterone mediates gene expression through regulation of various transcription factors, including NF-kappaB, STAT-3 and C/EBPalpha, and various steroid receptors such as androgen receptor and glucocorticoid receptors. Modulation of gene expression by guggulsterone leads to inhibition of cell proliferation, induction of apoptosis, suppression of invasion and abrogation of angiogenesis. Evidence has been presented to suggest that guggulsterone can suppress tumor initiation, promotion and metastasis. This review describes the identification of molecular targets of guggulsterone, cellular responses to guggulsterone, and animal studies and clinical trials of guggulsterone in cancer and other diseases.
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PMID:The guggul for chronic diseases: ancient medicine, modern targets. 1918 46


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