Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is well established that selective COX-2 inhibitors exhibit potent effects against progression of select solid tumours. However, their effects on liquid tumours have not been fully established. By taking advantage of murine Friend Disease we have shown a strong antileukemic effect of celecoxib by determining novel in vitro targets. Western blot analyses revealed the expression of COX-2 in a panel of Friend Virus-transformed, splenic-derived primary erythroleukemic blasts and established cell lines generated in our laboratory. We have shown that celecoxib at concentrations as low as 20 microM significantly suppresses proliferation of the selected murine erythroleukemia cell line HB60-5. The greatest proliferative inhibition was seen at 40 microM of celecoxib, resulting in apoptosis. Our results also demonstrate that treatment of the established murine erythroleukemia cell line HB60-5 with celecoxib results in suppression of c-Kit and erythropoietin receptor (Epo-R) phosphorylation resulting in apoptosis, likely through decreased levels of survival factors. However, upon overexpression of c-Kit alone in these cells a significant increase in survival and twofold increase in proliferation in the presence of celecoxib were observed (P < 0.05). Finally, since responsiveness of our murine erythroleukemia cell lines to celecoxib is above the reported physiologically achievable levels in vivo, we have provided in vitro evidence to suggest that reduced sensitivity of erythroleukemic cells to lower doses of celecoxib may be a consequence of the loss of wild-type p53. These findings are pivotal in addressing potential discrepancies associated with sensitivity of murine erythroleukemic cells to celecoxib in vitro versus in vivo.
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PMID:Phosphorylation status of c-Kit and Epo receptors, and the presence of wild-type p53 confer in vitro resistance of murine erythroleukemic cells to Celecoxib. 1474 7

The increased expression of cyclooxygenase (COX)-2 significantly enhances carcinogenesis and inflammatory reactions, and its regulation may be a reasonable target for cancer chemoprevention. We demonstrated previously that deguelin inhibits proliferation of premalignant human bronchial epithelial (HBE) cells, such as 1799 cells and squamous HBE cells, by regulating phosphatidylinositol-3-kinase Akt activity, which is involved in COX-2 expression. We sought to determine the effect of deguelin on COX-2 expression in squamous HBE cells. Deguelin strongly inhibited COX-2 expression in squamous HBE cells, without affecting the COX-1 protein level. Deguelin inhibited proliferation of a variety of non-small cell lung carcinoma (NSCLC) cell lines through apoptosis and induced Bax expression in the H322 NSCLC and squamous HBE cells. Deguelin treatment did not affect Bcl-2 protein levels but increased expression levels of the proapoptotic protein p53 and the cyclin-dependent kinase inhibitors p21 and p27 in the squamous HBE cells. The sensitivity of the squamous HBE and NSCLC cells to deguelin and the inhibitory effects of deguelin on COX-2 expression in the squamous HBE cells indicate that regulation of COX-2 expression is involved in the chemopreventive action of deguelin in lung cancer.
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PMID:Deguelin-induced inhibition of cyclooxygenase-2 expression in human bronchial epithelial cells. 1487 87

Gallbladder cancer (GBC) is the most common biliary tract malignancy. There is a tremendous regional variability in its incidence. Risk factors include genetic susceptibility, gender, presence of gallstones, chronic biliary infections, diet and some anatomical anomalies. Several genetic abnormalities have been described which may be aetiologically important as well as carry prognostic significance. These include mutations in the proteins K-RAS and P53, and altered expression of P-glycoprotein, COX-2 and epidermal growth factor receptor. Most patients present at an advanced stage, overall prognosis is very poor. TNM stage and the extent of surgical resection are the most important prognostic factors. Surgery is the only curative therapy reserved for patients with early-stage disease. The role of adjuvant therapy is not fully defined. Patients with advanced disease are managed with systemic chemotherapy that is primarily palliative. Although 5-fluorouracil alone, or in combination, has been most commonly utilised, there is much greater enthusiasm for the combination of cisplatin and gemcitabine. The availability of better drugs and combinations may affect the use of chemotherapy in neoadjuvant and adjuvant settings. Novel targeted therapies require exploration alone or in combination with chemotherapy.
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PMID:Gallbladder cancer: current status. 1516 72

Epidemiological evidence indicates that non-steroidal anti-inflammatory drugs (NSAIDs) protect against colorectal cancer (CRC) to a greater degree than other non-gastrointestinal cancers, but the molecular basis for this difference is unknown. We previously reported that aspirin induces signal-specific I kappa B alpha degradation followed by NF kappa B nuclear translocation in CRC cells, and that this mechanism contributes substantially to aspirin-induced apoptosis. Here, we explored the hypothesis that cell-type specific effects on NF kappa B signalling are responsible for the observed differences in protection by aspirin against CRC compared to breast and gynaecological cancers. We also assessed whether COX-2 expression, mutation status of adenomatous polyposis coli (APC), beta-catenin, p53, or DNA mismatch repair (MMR) genes in CRC lines influenced aspirin-induced effects. We found that aspirin induced concentration-dependent I kappa B alpha degradation, NF kappa B nuclear translocation and apoptosis in all CRC lines studied. However, there was no such effect on the other cancer cell types, indicating a considerable degree of cell-type specificity. The lack of effect on NF kappa B signalling, paralleled by absence of an apoptotic response to aspirin in non-CRC lines, strongly suggests a molecular rationale for the particular protective effect of NSAIDs against CRC. Effects on NF kappa B and apoptosis were observed irrespective of COX-2 expression, or mutation status in APC, beta-catenin, p53 and DNA MMR genes, underscoring the generality of the aspirin effect on NF kappa B in CRC cells. These findings raise the possibility of cell-type specific targets for the development of novel chemopreventive agents.
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PMID:Evidence for colorectal cancer cell specificity of aspirin effects on NF kappa B signalling and apoptosis. 1518

Both the availability of multiple treatment modalities and novel therapeutic targets make the correct prognostic stratification and the identification of truly predictive factors an issue of major debate in gastric cancer. Along with "classic" prognostic factors such as those related to the diffusion of the tumour at diagnosis (i.e., depth of gastric wall infiltration, locoregional lymph nodes or distant metastases) or those concerning the pathologic characteristics of the tumour, other, innovative, factors should be considered if a better definition of the characteristics of the tumour is to be given. These biological factors are often derived from the genetic process, which is thought to represent a crucial step to gastric cancer (DNA copy number changes, microsatellite instability, thymidilate synthase, E-cadherin, beta-catenin, mucin antigen, p53, c-erb B-2, COX-2, matrix metalloproteinases, VEGFR and EGFR). Some of those putative prognostic indicators can also be considered predictive of response to therapy as they are a molecular target either to chemotherapeutics (i.e., thymidilate synthase that is targeted by 5FU) or to a new class of antineoplastic molecules (i.e., c-erb B-2 targeted by trastuzumab, COX-2 by NSAIDs, matrix metalloproteinases, EGFR and VEGFR by specific inhibitors).
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PMID:Molecular biology of sporadic gastric cancer: prognostic indicators and novel therapeutic approaches. 1524 77

Colon cancer is the third most common cancer globally. The risk of developing colon cancer is influenced by a number of factors that include age and diet, but is primarily a genetic disease, resulting from oncogene over-expression and tumour suppressor gene inactivation. The induction and progression of the disease is briefly outlined, as are the cellular changes that occur in its progression. While colon cancer is uniformly amenable to surgery if detected at the early stages, advanced carcinomas are usually lethal, with metastases to the liver being the most common cause of death. Oncogenes and genetic mutations that occur in colon cancer are featured. The molecules and signals that act to eradicate or initiate the apoptosis cascade in cancer cells, are elucidated, and these include caspases, Fas, Bax, Bid, APC, antisense hTERT, PUMA, 15-LOX-1, ceramide, butyrate, tributyrin and PPARgamma, whereas the molecules which promote colon cancer cell survival are p53 mutants, Bcl-2, Neu3 and COX-2. Cancer therapies aimed at controlling colon cancer are reviewed briefly.
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PMID:Colon cancer: genomics and apoptotic events. 1525 76

The role of glutathione S-transferase pi (GSTpi) in tumor development has been previously suggested; however the exact function of this enzyme in carcinogenesis remains unclear. GSTpi has been identified as a modulator of cell signaling by interacting with and inhibiting c-Jun N-terminal kinase (JNK). This kinase has been in turn described as a regulator of p53 stability and transcriptional activity. To study the possible interaction between GSTpi and p53, we crossed GSTpi-deficient animals with p53(-/-) mice. Double knock out animals were viable but developed tumors within 6 months of age; the life span of these animals was however similar to that of GSTpi(+/-)/p53(-/-) and GSTpi(+/+)/p53(-/-). Mice heterozygous for p53 lived significantly longer than the p53(-/-) animals and developed tumors much later, and the expression of GSTpi did not significantly modify the life span of the animals. In contrast, in a wild-type p53 background, GSTpi(-/-) mice developed tumors with a significantly higher frequency than heterozygous and wild-type animals with a median tumor free life span 20 weeks shorter. In addition, in p53(+/+) background, one third of the GSTpi(-/-) animals developed lung adenomas, while less than 10% of GSTpi(+/-) and GSTpi(+/+) presented such tumors. GSTpi expression did not alter the expression of tumorigenesis markers such as COX-2 or ornithine decarboxylase in response to phorbol ester. Furthermore, GSTpi-deficient mouse embryo fibroblasts were more sensitive to H(2)O(2)-induced apoptosis. P53(-/-) cells, independent of GSTpi status, were more sensitive to UV and other DNA damaging agents than their wild-type counterparts. These results suggest that GSTpi may play a protective role in the development of spontaneous tumors.
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PMID:Influence of glutathione S-transferase pi and p53 expression on tumor frequency and spectrum in mice. 1538 26

Nitric oxide (NO) is a pleiotrophic regulator, pivotal to numerous biological processes, including vasodilation, neurotransmission, and macrophage-mediated immunity. The highly reactive free radicals, produced by NO synthases (NOS) have been implicated in the modulation of carcinogenesis. Over-expression of inducible NOS (iNOS), a common phenomenon during chronic inflammatory conditions, generates sustainable amounts of NO, that its reactive intermediates are mutagenic, causing DNA damage or impairment of DNA repair, has been well established in carcinogenesis. Recent studies also implicate NO as having a key signaling molecule that regulates processes of tumorigenesis. Increased expression of iNOS has been observed in tumors of the colon, lung, oropharynx, reproductive organs, breast, and central nervous system besides its occurrence in chronic inflammatory diseases. Progression of a large majority of human and experimental colon tumors appears to progress by NO resulting from stimulation of proinflammatory cytokines, and inactivation (nitrosylation) of p53 mediated caspase activities in the tumors, whereas in some cases it associated with induction of apoptosis and tumor regression. This dichotomy is largely explained by the complexity of signaling pathways in tumor cells, that respond to NO very differently depending on its concentration. p53 mutation, functional loss, activation, and inactivation of apoptotic proteins all have been linked with NO resistance and dependence. Evidence from both in vitro and in vivo experiments support that NO and its reactive metabolite peroxynitrite stimulate COX-2 activity leading generation of tumor growth enhancing prostaglandins. Thus, NO mediated signaling can augment the tumor growth and metastasis by promoting invasive and angiogenic properties of tumor cells, which includes triggering and activation of COX-2. Thus, developing selective inhibitors of iNOS and NO-releasing agents may lead to important strategies for chemoprevention of colon cancer. Chemoprevention studies at preclinical level with several selective inhibitors of iNOS in both chemically and transgenic models of colon cancer are encouraging.
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PMID:Nitric oxide signaling in colon cancer chemoprevention. 1547 55

Resveratrol, trans-3,5,4'-trihydroxystilbene, was first isolated in 1940 as a constituent of the roots of white hellebore (Veratrum grandiflorum O. Loes), but has since been found in various plants, including grapes, berries and peanuts. Besides cardioprotective effects, resveratrol exhibits anticancer properties, as suggested by its ability to suppress proliferation of a wide variety of tumor cells, including lymphoid and myeloid cancers; multiple myeloma; cancers of the breast, prostate, stomach, colon, pancreas, and thyroid; melanoma; head and neck squamous cell carcinoma; ovarian carcinoma; and cervical carcinoma. The growth-inhibitory effects of resveratrol are mediated through cell-cycle arrest; upregulation of p21Cip1/WAF1, p53 and Bax; down-regulation of survivin, cyclin D1, cyclin E, Bcl-2, Bcl-xL and clAPs; and activation of caspases. Resveratrol has been shown to suppress the activation of several transcription factors, including NF-kappaB, AP-1 and Egr-1; to inhibit protein kinases including IkappaBalpha kinase, JNK, MAPK, Akt, PKC, PKD and casein kinase II; and to down-regulate products of genes such as COX-2, 5-LOX, VEGF, IL-1, IL-6, IL-8, AR and PSA. These activities account for the suppression of angiogenesis by this stilbene. Resveratrol also has been shown to potentiate the apoptotic effects of cytokines (e.g., TRAIL), chemotherapeutic agents and gamma-radiation. Phamacokinetic studies revealed that the target organs of resveratrol are liver and kidney, where it is concentrated after absorption and is mainly converted to a sulfated form and a glucuronide conjugate. In vivo, resveratrol blocks the multistep process of carcinogenesis at various stages: it blocks carcinogen activation by inhibiting aryl hydrocarbon-induced CYP1A1 expression and activity, and suppresses tumor initiation, promotion and progression. Besides chemopreventive effects, resveratrol appears to exhibit therapeutic effects against cancer. Limited data in humans have revealed that resveratrol is pharmacologically quite safe. Currently, structural analogues of resveratrol with improved bioavailability are being pursued as potential therapeutic agents for cancer.
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PMID:Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. 1551 85

Although p53-inactivating mutations have been described in the majority of human cancers, their role in prostate cancer is controversial as mutations are uncommon, particularly in early lesions. p53 is activated by hypoxia and other stressors and is primarily regulated by the Mdm2 protein. Cyclooxygenase (COX)-2, an inducible enzyme that catalyzes the conversion of arachidonic acid to prostaglandins and other eicosanoids, is also induced by hypoxia. COX-2 and resultant prostaglandins increase tumor cell proliferation, resistance to apoptosis, and angiogenesis. Previous reports indicate a complex, reciprocal relationship between p53 and COX-2. To elucidate the effects of COX-2 on p53 in response to hypoxia, we transfected the COX-2 gene into the p53-positive, COX-2-negative MDA-PCa-2b human prostate cancer cell line. The expression of functional p53 and Mdm2 was compared in COX-2+ versus COX-2- cells under normoxic and hypoxic conditions. Our results demonstrated that hypoxia increases both COX-2 protein levels and p53 transcriptional activity in these cells. Forced expression of COX-2 increased tumor cell viability and decreased apoptosis in response to hypoxia. COX-2+ cells had increased Mdm2 phosphorylation in either normoxic or hypoxic conditions. Overexpression of COX-2 abrogated hypoxia-induced p53 phosphorylation and promoted the binding of p53 to Mdm2 protein in hypoxic cells. In addition, COX-2-expressing cells exhibited decreased hypoxia-induced nuclear accumulation of p53 protein. Finally, forced expression of COX-2 suppressed both basal and hypoxia-induced p53 transcriptional activity, and this effect was mimicked by the addition of PGE2 to wild-type cells. These results demonstrated a role for COX-2 in the suppression of hypoxia-induced p53 activity via both direct effects and indirect modulation of Mdm2 activity. These data imply that COX-2-positive prostate cancer cells can have impaired p53 function even in the presence of wild-type p53 and that p53 activity can be restored in these cells via inhibition of COX-2 activity.
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PMID:Cyclooxygenase-2 suppresses hypoxia-induced apoptosis via a combination of direct and indirect inhibition of p53 activity in a human prostate cancer cell line. 1555 Apr


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