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)

Substantial evidence indicates that the cyclo-oxygenase-2 (COX-2) inhibitor celecoxib, a widely prescribed anti-inflammatory agent, displays anti-tumour effect by sensitizing cancer cells to apoptosis. As part of our effort to understand the mechanism by which celecoxib mediates apoptosis in androgen-independent prostate cancer cells, we investigated its effect on intracellular calcium concentration ([Ca(2+)](i)). Digital ratiometric imaging analysis indicates that exposure of PC-3 cells to celecoxib stimulates an immediate [Ca(2+)](i) rise in a dose- and time-dependent manner. Kinetic data show that this Ca(2+) signal arises from internal Ca(2+) release in conjunction with external Ca(2+) influx. Examinations of the biochemical mechanism responsible for this Ca(2+) mobilization indicate that celecoxib blocks endoplasmic reticulum (ER) Ca(2+)-ATPases. Consequently, inhibition of this Ca(2+) reuptake mechanism results in Ca(2+) mobilization from ER stores followed by capacitative calcium entry, leading to [Ca(2+)](i) elevation. In view of the important role of Ca(2+) in apoptosis regulation, this Ca(2+) perturbation may represent part of the signalling mechanism that celecoxib uses to trigger rapid apoptotic death in cancer cells. This Ca(2+)-ATPase inhibitory activity is highly specific for celecoxib, and is not noted with other COX inhibitors tested, including aspirin, ibuprofen, naproxen, rofecoxib (Vioxx), DuP697 and NS398. Moreover, it is noteworthy that this activity is also observed in many other cell lines examined, including A7r5 smooth muscle cells, NIH 3T3 fibroblast cells and Jurkat T cells. Consequently, this Ca(2+)-perturbing effect may provide a plausible link with the reported toxicities of celecoxib such as increased cardiovascular risks in long-term anti-inflammatory therapy.
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PMID:The cyclo-oxygenase-2 inhibitor celecoxib perturbs intracellular calcium by inhibiting endoplasmic reticulum Ca2+-ATPases: a plausible link with its anti-tumour effect and cardiovascular risks. 1207 51

To test our hypothesis that Cyclooyxgenase-2 (COX-2) inhibitors would stop the growth of breast and prostate cancer cells in vitro, two breast (MCF-7, ZR75-1) and two prostate cancer cell lines (PC-3, DU145) were treated with rofecoxib (Vioxx) or NS398. Cell growth was measured by MTT at 24 and 72 hours. Statistical analysis was performed by ANOVA. Significant growth inhibition (p < 0.05) was observed in all cell lines in a dose-dependent manner after treatment with COX-2 inhibitors. Rofecoxib inhibited cellular proliferation by inducing (p < 0.001) apoptosis in breast cancer cells. Our study indicates that COX-2 inhibition reduces the growth of human breast and prostate cancer in vitro. Human studies are needed to evaluate the clinical utility of rofecoxib treatment in breast or prostate cancers.
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PMID:COX-2 inhibition and cancer: experimental findings and clinical correlates. 1538 41

Certain lactone-containing secondary plant metabolites display potent biological effects, including anti-tumor activities. This is of particular interest as these compounds appear effective against hormone-dependent cancers, such as those of breast and prostate, of which the incidence is on the rise. The mechanisms of anti-tumor action of these compounds are largely unknown. Thirteen synthetic lactone derivatives were evaluated for effects on aromatase activity and mRNA expression in H295R human adrenocortical carcinoma cells. Aromatase (CYP19) is a key enzyme in the synthesis of estrogens from androgens. Over-expression has been associated with increased risk of developing estrogen-dependent mammary tumors, and aromatase inhibitors are effective in their treatment. The androgen receptor is implicated in mediating hormone-dependent prostate tumor growth, and androgen antagonists are effective in the treatment of these cancers. Thus the (anti)androgenic effects of the lactones were also assessed in LNCaP human prostate cancer cells transfected with human androgen receptor and an androgen receptor-responsive luciferase reporter gene. Cells were exposed to lactones (0.1-100 microM) dissolved in dimethyl sulfoxide (0.1% in medium) for 24 h prior to measurement of aromatase activity using a tritiated water-release assay. Three (competitive) inhibitors of aromatase activity were identified (potencies in decreasing order): 3-(3,4-dimethoxy-phenyl)-4-(4-methoxy-phenyl)-5H-furan-2-one (CRI-7; IC(50)=1 microM; K(i)=1.0 microM), 3,4-bis-(3,4-dimethoxy-phenyl)-5H-furan-2-one (CRI-8; IC(50)=2 microM; K(i)=1.2 microM) and 3-(3,4-dimethoxy-phenyl)-4-(3,4,5-trimethoxy-phenyl)-5H-furan-2-one (CRI-9; IC(50)=3 microM; K(i)=6.8 microM). Several concentration-dependent inducers of aromatase (>2fold) were also identified (CRI-1, CRI-4 or Vioxx, CRI-11 and CRI-13). These lactones also induced pII promoter-specific CYP19 transcripts. In transfected LNCaP cells, the three aromatase inhibitors CRI-7, 8 and 9 demonstrated concentration-dependent anti-androgenicity above 0.1 microM in the presence of either 0.1 nM of dihydrotestosterone or the synthetic androgen R1881. The other lactones showed no consistent pro- or anti-androgenic effects in these LNCaP cells. Lactone moiety-containing molecules may form the structural basis for the development of potent drugs effective against hormone-dependent cancers.
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PMID:Effects of lactone derivatives on aromatase (CYP19) activity in H295R human adrenocortical and (anti)androgenicity in transfected LNCaP human prostate cancer cells. 1863 41