Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostaglandins are synthesized from arachidonic acid by the enzyme cyclo-oxygenase. There are two isoforms of cyclooxygenases: COX-1 (a constitutive form) and COX-2 (an inducible form). COX-2 has recently been categorized as an immediate-early gene and is associated with cellular growth and differentiation. The purpose of this study was to investigate the effects of exogenous dimethylprostaglandin E2 (dmPGE2) on prostate cancer cell growth. Results of these experiments demonstrate that administration of dmPGE2 to growing PC-3 cells significantly increased cellular proliferation (as measured by the cell number), total DNA content and endogenous PGE2 concentration. DmPGE2 also increased the steady-state mRNA levels of its own inducible synthesizing enzyme, COX-2, as well as cellular growth to levels similar to those seen with fetal calf serum and phorbol ester. The same results were observed in other human cancer cell types, such as the androgen-dependent LNCaP cells, breast cancer MDA-MB-134 cells and human colorectal carcinoma DiFi cells. In PC-3 cells, the dmPGE2 regulation of the COX-2 mRNA levels was both time dependent, with maximum stimulation seen 2 h after addition, and dose dependent on dmPGE2 concentration, with maximum stimulation seen at 5 microg ml(-1). The non-steroidal anti-inflammatory drug flurbiprofen (5 microM), in the presence of exogenous dmPGE2, inhibited the up-regulation of COX-2 mRNA and PC-3 cell growth. Taken together, these data suggest that PGE2 has a specific role in the maintenance of human cancer cell growth and that the activation of COX-2 expression depends primarily upon newly synthesized PGE2, perhaps resulting from changes in local cellular PGE2 concentrations.
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PMID:Induction of cyclo-oxygenase-2 mRNA by prostaglandin E2 in human prostatic carcinoma cells. 909 57

We examined the activity of two metabolites of sulindac (a nonsteroidal anti-inflammatory drug), sulindac sulfide and sulindac sulfone (exisulind, Prevatec), and a novel highly potent analog of exisulind (CP248) on a series of human prostate epithelial cell lines. Marked growth inhibition was seen with the BPH-1, LNCaP, and PC3 cell lines with IC50 values of about 66 microM, 137 microM, and 64 nM for sulindac sulfide, exisulind, and CP248, respectively. DNA flow cytometry and 4',6'-diamido-2-phenylindole (DAPI) staining indicated that these three compounds also induced apoptosis in all of these cell lines. Similar growth inhibition also was seen with the PrEC normal human prostate epithelial cell line, but these cells were resistant to induction of apoptosis at concentrations up to 300 microM, 1 mM, and 750 nM of sulindac sulfide, exisulind, and CP248, respectively. Derivatives of LNCaP cells that stably overexpress bcl-2 remained sensitive to growth inhibition and induction of apoptosis by these compounds. In vitro enzyme assays indicated that despite its high potency in inhibiting growth and inducing apoptosis, CP248, like exisulind, lacked cyclooxygenase (COX-1 and COX-2) inhibitory activity even at concentrations up to 10 mM. Moreover, despite variations of COX-1 and COX-2 expression, the three benign and malignant prostate cell lines showed similar sensitivity to growth inhibition and induction of apoptosis by these three compounds. Therefore, sulindac derivatives can cause growth inhibition and induce apoptosis in human prostate cancer cells by a COX-1 and -2 independent mechanism, and this occurs irrespective of androgen sensitivity or increased expression of bcl-2. These compounds may be useful in the prevention and treatment of human prostate cancer.
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PMID:Sulindac derivatives inhibit growth and induce apoptosis in human prostate cancer cell lines. 1048 67

More than 40 promising agents and agent combinations are being evaluated clinically as chemopreventive drugs for major cancer targets. A few have been in vanguard, large-scale intervention trials--for example, the studies of tamoxifen and fenretinide in breast, 13-cis-retinoic acid in head and neck, vitamin E and selenium in prostate, and calcium in colon. These and other agents are currently in phase II chemoprevention trials to establish the scope of their chemopreventive efficacy and to develop intermediate biomarkers as surrogate end points for cancer incidence in future studies. In this group are fenretinide, 2-difluoromethylornithine, and oltipraz. Nonsteroidal anti-inflammatories (NSAID) are also in this group because of their colon cancer chemopreventive effects in clinical intervention, epidemiological, and animal studies. New agents are continually considered for development as chemopreventive drugs. Preventive strategies with antiandrogens are evolving for prostate cancer. Anti-inflammatories that selectively inhibit inducible cyclooxygenase (COX)-2 are being investigated in colon as alternatives to the NSAID, which inhibit both COX-1 and COX-2 and derive their toxicity from COX-1 inhibition. Newer retinoids with reduced toxicity, increased efficacy, or both (e.g., 9-cis-retinoic acid) are being investigated. Promising chemopreventive drugs are also being developed from dietary substances (e.g., green and black tea polyphenols, soy isoflavones, curcumin, phenethyl isothiocyanate, sulforaphane, lycopene, indole-3-carbinol, perillyl alcohol). Basic and translational research necessary to progress in chemopreventive agent development includes, for example, (1) molecular and genomic biomarkers that can be used for risk assessment and as surrogate end points in clinical studies, (2) animal carcinogenesis models that mimic human disease (including transgenic and gene knockout mice), and (3) novel agent treatment regimens (e.g., local delivery to cancer targets, agent combinations, and pharmacodynamically guided dosing).
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PMID:Progress in cancer chemoprevention. 1066 77

Prostate cancer cells are known to express cyclooxygenases (COXs) and synthesize prostaglandins. Catabolism of prostaglandins in these cells remains to be determined. Induction of NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a key metabolic inactivation enzyme, was investigated in androgen-sensitive LNCaP cells and in hormone-independent PC3 cells. 15-PGDH was found to be induced by dihydrotestosterone or testosterone in a time- and dose-dependent manner in LNCaP but not in PC3 cells as shown by activity assay and immunoblot analysis. However, prostaglandin synthetic enzymes, COX-1 and COX-2, were not found to be induced by androgens. Induction was also achieved by 17beta-estradiol and progesterone, although to a lesser extent. Induction of 15-PGDH was not blocked by steroid receptor antagonist, RU 486, nor by antiandrogen, flutamide. However, induction was inhibited by tyrosine kinase inhibitor, genistein, and by ERK kinase inhibitor, PD 98059, but not by protein kinase C inhibitor, GF109203X. These results suggest that androgens induce 15-PGDH gene expression through an unconventional nongenomic pathway.
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PMID:Induction of NAD(+)-linked 15-hydroxyprostaglandin dehydrogenase expression by androgens in human prostate cancer cells. 1100 85

Several types of human tumors overexpress cyclooxygenase (COX) -2 but not COX-1, and gene knockout transfection experiments demonstrate a central role of COX-2 in experimental tumorigenesis. COX-2 produces prostaglandins that inhibit apoptosis and stimulate angiogenesis and invasiveness. Selective COX-2 inhibitors reduce prostaglandin synthesis, restore apoptosis, and inhibit cancer cell proliferation. In animal studies they limit carcinogen-induced tumorigenesis. In contrast, aspirin-like nonselective NSAIDs such as sulindac and indomethacin inhibit not only the enzymatic action of the highly inducible, proinflammatory COX-2 but the constitutively expressed, cytoprotective COX-1 as well. Consequently, nonselective NSAIDs can cause platelet dysfunction, gastrointestinal ulceration, and kidney damage. For that reason, selective inhibition of COX-2 to treat neoplastic proliferation is preferable to nonselective inhibition. Selective COX-2 inhibitors, such as meloxicam, celecoxib (SC-58635), and rofecoxib (MK-0966), are NSAIDs that have been modified chemically to preferentially inhibit COX-2 but not COX-1. For instance, meloxicam inhibits the growth of cultured colon cancer cells (HCA-7 and Moser-S) that express COX-2 but has no effect on HCT-116 tumor cells that do not express COX-2. NS-398 induces apoptosis in COX-2 expressing LNCaP prostate cancer cells and, surprisingly, in colon cancer S/KS cells that does not express COX-2. This effect may due to induction of apoptosis through uncoupling of oxidative phosphorylation and down-regulation of Bcl-2, as has been demonstrated for some nonselective NSAIDs, for instance, flurbiprofen. COX-2 mRNA and COX-2 protein is constitutively expressed in the kidney, brain, spinal cord, and ductus deferens, and in the uterus during implantation. In addition, COX-2 is constitutively and dominantly expressed in the pancreatic islet cells. These findings might somewhat limit the use of presently available selective COX-2 inhibitors in cancer prevention but will probably not deter their successful application for the treatment of human cancers.
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PMID:Biochemistry of cyclooxygenase (COX)-2 inhibitors and molecular pathology of COX-2 in neoplasia. 1107 56

Cyclooxygenase (COX)-2 expression is elevated in some malignancies; however, information is scarce regarding COX-2 contributions to the development of prostate cancer and its regulation by inflammatory cytokines. The present study compared and contrasted the expression levels and subcellular distribution patterns of COX-1 and COX-2 in normal prostate [prostate epithelial cell (PrEC), prostate smooth muscle (PrSM), and prostate stromal (PrSt)] primary cell cultures and prostatic carcinoma cell lines (PC-3, LNCaP, and DU145). The basal COX-2 mRNA and protein levels were high in normal PrEC and low in tumor cells, unlike many other normal cells and tumor cells. Because COX-2 levels were low in prostate smooth muscle cells, prostate stromal cells, and tumor cells, we also examined whether COX-1 and COX-2 gene expression was elevated in response to tumor necrosis factor-alpha (TNF-alpha), a strong inducer of COX-2 expression. Northern blot analysis and reverse transcription-PCR demonstrated different patterns and kinetics of expression for COX-1 and COX-2 among normal cells and tumor cells in response to TNF-alpha. In particular, COX-2 protein levels increased, and the subcellular distribution formed a distinct perinuclear ring in the normal cells at 4 h after TNF-alpha exposure. The COX-2 protein levels also increased in cancer cells, but the subcellular distribution was less organized; COX-2 protein appeared diffuse in some cells and accumulated as focal deposits in the cytoplasm of other cells. TNF-alpha induction of COX-2 and prostaglandin E2 correlated inversely with induction of apoptosis. We conclude that COX-2 expression may be important to PrEC cell function. Although it is low in stromal and tumor cells, COX-2 expression is induced by TNF-alpha in these cells, and this responsiveness may play an important role in prostate cancer progression.
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PMID:Differential expression of cyclooxygenase-2 and its regulation by tumor necrosis factor-alpha in normal and malignant prostate cells. 1128 53

Aspirin and the nonsteroidal anti-inflammatory drugs (NSAIDs) have been commercially available for decades, and their ability to reduce pain and inflammation are well known. The ability of these agents to cause adverse effects are also known, and the search for newer NSAIDs with less side effects accelerated after the two isoforms of cyclooxygenase (COX) (COX-1 and COX-2) were discovered. The selective COX-2 inhibitors seem to have equivalent efficacy, but potentially less gastrointestinal adverse effects than the traditional NSAIDs. Recent concern that the selective COX-2 inhibitors could increase cardiovascular events requires more investigation. In the meantime, aspirin continues to receive attention as a potential primary cardiovascular agent because of its antiplatelet effects and past and current clinical trials. Several trials have demonstrated that low-dose aspirin may significantly reduce the risk of myocardial infarction and other cardiovascular events. However, the benefits of aspirin need to be weighed against its primary side effect in these situations (hemorrhagic stroke). Patients at low risk for future cardiovascular events are probably not good candidates for this therapy; however, those individuals with a high risk of a future cardiovascular event may qualify for this therapy. Aspirin has also demonstrated a potential ability to reduce the risk of deep venous thrombosis and pulmonary embolism. A recent large trial of low-dose aspirin after major surgery revealed that this agent could also have some activity in the venous component of the human body. Aspirin may also have some applicability for reducing side effects of oral estrogens in men with advanced prostate cancer. Thus, it seems as if aspirin, NSAIDS, and even the selective COX-2 inhibitors may have therapeutic potential far beyond reducing pain and general inflammation. These overall observations and effects provided some of the impetus to investigate their potential ability to reduce the risk and possibly progression of a number of cancers. A few already available over-the-counter products and prescriptions seem to be receiving attention as possible anticancer agents.
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PMID:An introduction to aspirin, NSAIDs, and COX-2 inhibitors for the primary prevention of cardiovascular events and cancer and their potential preventive role in bladder carcinogenesis: part I. 1176 81

Experiments were conducted to determine the effects of novel anti-neoplastic isochalcones (DJ compounds), on cyclooxyegenase 1 and 2 (COX-1 and COX-2) enzyme expression in androgen receptor dependent human prostate cancer cell line LNCaP. Results from Western blot analysis and cell flow cytometry showed that DJ52 and DJ53 decreased the steady state levels of COX-1 and COX-2 protein levels in a dose dependent manner. In addition, DJ52 and DJ53 decreased the levels of epidermal growth factor (EGF) in LNCaP cells. In this study, we report that novel isochalcones decreased COX-1, COX-2 and EGF levels as well as LNCaP cellular growth in a dose responsive manner. Our findings indicate that relative decreases in COX-1, COX-2 and EGF expressions might serve as indicators of tumor growth inhibition in prostate neoplasms.
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PMID:Novel antineoplastic isochalcones inhibit the expression of cyclooxygenase 1,2 and EGF in human prostate cancer cell line LNCaP. 1178 54

It is well known that about 70% of cancer cases are due to environmental, dietary, or lifestyle factors. Accordingly, these cases maybe avoided by appropriate modifications. In addition, active chemoprevention has become a major interventional approach following the epidemiological observation of a beneficial effect of nonsteroidal anti-inflammatory drugs (NSAIDs) in colon cancer prevention. This is chiefly due to the inhibition of the cyclooxygenase (COX) enzymes. The COX enzymatic system includes two isoenzymes, COX-1 and COX-2, that convert arachidonic acid to prostaglandins. COX-1 is constitutively expressed and synthesizes cytoprotective prostaglandins in the gastrointestinal tract. COX-2 is inducible by the oncogenes ras and scr and other cytokines; it is overexpressed in human cancer cells in which it stimulates cellular division and angiogenesis and inhibits apoptosis. NSAIDs restore apoptosis and decrease tumor mitogenesis and angiogenesis. Most cancer cells have been found to exhibit overexpression of COX-2. Epidemiological studies showed a lower risk of developing cancer of the colon, breast, esophagus, and stomach following the ingestion of NSAIDs. The use of NSAIDs in low dose was associated with a statistically significant decrease in the risk of adenomatous polyps and of overt colon cancer. The regressive effects of sulindac on foci of aberrant crypts in the colon (considered to be precursors of adenoma), and on adenocarcinoma of the colon, are of particular interest because this NSAID does not have an inhibitory effect on COX. This may support the view that the antineoplastic effect of NSAIDs may also be due to a mechanism other than COX-2 inhibition. In breast cancer, large cohort studies reported a 40 to 50% reduced risk of developing cancer, a smaller size of the primary tumor, and a reduction in the number of involved axillary lymph nodes. Similar findings have been reported in the esophagus and stomach, but not in gastric cardia adenocarcinoma. The recent development of selective COX-2 inhibitors resulted in better clinical tolerance than that associated with NSAIDs in general, with the absence of gastrointestinal side effects known to occur after the inhibition of COX-1. Encouraging results have been obtained with these new agents in familial adenomatous polyposis, colon, breast, and prostate cancer.
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PMID:Epidemiological and clinical aspects of nonsteroidal anti-inflammatory drugs and cancer risks. 1208 6

In recent years a dramatic surge has occurred on studies defining to the role of cyclooxygenase (COX)-2 in causation and prevention of cancer. Prostaglandin (PG) endoperoxidase synthase also commonly referred to as COX is a key enzyme involved in the conversion of arachidonic acid to PGs and other eicosanoids. COX exists as two isoforms, namely COX-1 and COX-2 with distinct tissue distribution and physiological functions. COX-1 is constitutively expressed in many tissues and cell types and is involved in normal cellular physiological functions whereas COX-2 is pro-inflammatory in nature and is inducible by mitogens, cytokines, tumor promoters and growth factors. A large volume of data exists showing that COX-2 is overexpressed in a large number of human cancers and cancer cell lines. The possibility of COX-2 as a candidate player in cancer development and progression evolved from the epidemiological studies which suggest that regular use of aspirin or other non-steroidal anti-inflammatory drugs could significantly decrease the risk of developing cancers in experimental animals and in humans. In our recently published study (Prostate, 42 2000 73-78), we provided the first evidence that COX-2 is overexpressed in human prostate adenocarcinoma. Many other studies verified our initial observation and reported that compared to normal tissue, COX-2 is overexpressed in human prostate cancer. It should be noted that some recent work has suggested that COX-2 is only up-regulated in proliferative inflammatory atrophy of the prostate, but not in prostate carcinoma. In this scenario, COX-2 inhibitors could afford their effects against prostate carcinogenesis by modulating COX-2 activity in other cells in prostate. An exciting corollary to this ongoing work is that selective COX-2 inhibitors may exhibit chemopreventive and even chemotherapeutic effects against prostate carcinogenesis in humans.
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PMID:Cyclooxygenase-2 and prostate carcinogenesis. 1261 25


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