leukotriene-b4 and Prostatic-Neoplasms

We previously reported that a 4- to 6-week low-fat fish oil (LFFO) diet did not affect serum insulin-like growth factor (IGF)-1 levels (primary outcome) but resulted in lower omega-6 to omega-3 fatty acid ratios in prostate tissue and lower prostate cancer proliferation (Ki67) as compared with a Western diet. In this post hoc analysis, the effect of the LFFO intervention on serum pro-inflammatory eicosanoids, leukotriene B4 (LTB4) and 15-S-hydroxyeicosatetraenoic acid [15(S)-HETE], and the cell-cycle progression (CCP) score were investigated. Serum fatty acids and eicosanoids were measured by gas chromatography and ELISA. CCP score was determined by quantitative real-time reverse transcriptase PCR (RT-PCR). Associations between serum eicosanoids, Ki67, and CCP score were evaluated using partial correlation analyses. BLT1 (LTB4 receptor) expression was determined in prostate cancer cell lines and prostatectomy specimens. Serum omega-6 fatty acids and 15(S)-HETE levels were significantly reduced, and serum omega-3 levels were increased in the LFFO group relative to the Western diet group, whereas there was no change in LTB4 levels. The CCP score was significantly lower in the LFFO compared with the Western diet group. The 15(S)-HETE change correlated with tissue Ki67 (R = 0.48; P < 0.01) but not with CCP score. The LTB4 change correlated with the CCP score (r = 0.4; P = 0.02) but not with Ki67. The LTB4 receptor BLT1 was detected in prostate cancer cell lines and human prostate cancer specimens. In conclusion, an LFFO diet resulted in decreased 15(S)-HETE levels and lower CCP score relative to a Western diet. Further studies are warranted to determine whether the LFFO diet antiproliferative effects are mediated through the LTB4/BLT1 and 15(S)-HETE pathways.

Topics: Aged; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Diet, Fat-Restricted; Disease Progression; Eicosanoids; Fatty Acids; Fish Oils; Gene Expression Regulation, Neoplastic; Humans; Hydroxyeicosatetraenoic Acids; Inflammation; Insulin-Like Growth Factor I; Ki-67 Antigen; Leukotriene B4; Male; Middle Aged; Prostatectomy; Prostatic Neoplasms; Receptors, Leukotriene B4

Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, has anticancer effect on many cancers associated with chronic inflammation by both COX-2-dependent and COX-2-independent mechanisms. The non-COX-2 targets of celecoxib, however, are still a matter of research. Leukotriene B4 (LTB4) has been implicated in prostate and colon carcinogenesis, but little is known about the potential role of LTB4 in celecoxib-mediated anticancer effect. In this study, we evaluated whether LTB4 was involved in celecoxib-mediated inhibitory effect on human colon cancer HT-29 cells and human prostate cancer PC-3 cells. Our data showed that survival of both cell lines was obviously suppressed after celecoxib treatment for 72 h in a concentration-dependent manner. However, only in HT-29 cells, this inhibitory effect could be reversed by LTB4, which promoted survival of HT-29 cells rather than PC-3 cells. Consistent with these results, lioxygenase (LOX) potent inhibitor nordihydroguaiaretic acid (NDGA) had a higher inhibitory effect on HT-29 cells than PC-3 cells. Additionally, ELISA results showed that celecoxib could suppress expression of LTB4 in both cell lines, whereas, inhibition of PGE2 was only detected in HT-29 cells. These results indicate that the anticancer effect of celecoxib is COX-2-independent in HT-29 and PC-3 cells and in HT-29 cells primarily via down-regulating LTB4 production.

Topics: Antineoplastic Agents; Celecoxib; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colonic Neoplasms; Cyclooxygenase 2 Inhibitors; Humans; Leukotriene B4; Lipoxygenase Inhibitors; Male; Masoprocol; Prostatic Neoplasms; Pyrazoles; Sulfonamides

PGE2 and LTB4 are involved in inflammation and carcinogenesis in several tissues but have not been studied in prostate cancer and hyperplasia until now. We therefore measured PGE2 and LTB4 productions in a total of 206 prostate tissues from 116 patients including benign hyperplastic (90), pericancerous (106) and cancerous samples (10). We also analysed the influence of inflammation levels, prostate volume and glandular to epithelial ratio. PGE2 and LTB4 concentrations were measured using specific enzyme immunoassay kits. There was a correlation between PGE2 level, prostatic volume, inflammation score, and decreased glandular surface. By contrast, there was no correlation between LTB4 levels and inflammation or PGE2 production. Cancerous samples had higher LTB4 levels than pericancerous samples, but there was no difference in PGE2 levels. PGE2 and inflammation may be associated to stromal benign prostatic hyperplasia whereas LTB4 may play a role in prostate carcinogenesis.

Topics: Adult; Aged; Aged, 80 and over; Dinoprostone; Humans; Inflammation; Leukotriene B4; Male; Middle Aged; Organ Size; Prostatic Hyperplasia; Prostatic Neoplasms

Recent clinical trials have documented that selenium significantly reduces the incidence of clinical prostate cancer. However, nothing is clearly known about the underlying molecular mechanisms by which selenium exerts its anti-cancer effect. This report provides evidence that selenium at micro-molar concentrations induces rapid apoptotic death in human prostate cancer cells, but not in normal prostate epithelial cells. Apoptosis involves activation of caspase 3 which plays a critical role in the cell death process. Interestingly, the apoptosis-inducing effect of selenium in prostate cancer cells is substantially alleviated by the 5-lipoxygenase metabolites, 5(S)-HETE and its dehydrogenated derivative 5-oxoETE, but not by metabolites of 12-lipoxygenase (12(S)-HETE) or 15-lipoxygenase (15(S)-HETE). Apoptosis is also prevented by their precursor, arachidonic acid, an omega-6, polyunsaturated fatty acid, presumably by metabolic conversion through the 5-lipoxygenase pathway. These results indicate that selenium's anticancer effect may involve induction of apoptosis specifically in prostate cancer cells sparing normal prostate epithelial cells, and that 5-lipoxygenase may be a molecular target of selenium's anticancer action. The present report warrants that care should be taken about high intake of dietary fat containing arachidonic acid or its precursor fatty acids when selenium is used for the management of prostate cancer, and suggests that a combination of selenium and 5-lipoxygenase inhibitors may be a more effective regimen for prostate cancer control.

Topics: Apoptosis; Arachidonate 5-Lipoxygenase; Arachidonic Acid; Caspase Inhibitors; Caspases; Cell Division; Cell Line, Tumor; Cysteine Proteinase Inhibitors; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Lipoxygenase Inhibitors; Male; Oligopeptides; Prostatic Neoplasms; Selenium

Non-invasive diagnostic tools to evaluate the severity of acute, radiation-induced proctitis are not readily available. The faecal excretion of eight markers of gut inflammation was therefore examined. Five proteins and three lipid derivates were analysed in sequential stool samples taken before and during radiation therapy.. Stool samples from 15 patients with prostate cancer scheduled for radiation therapy were examined. Pretreatment and in-treatment samples (2nd and 6th weeks) were measured by enzyme-linked immunosorbent assay (ELISA) (calprotectin, lactoferrin, transferrin, leukotriene B4, prostaglandin E2, thromboxane B2 and TNF alpha) or nephelometry (alpha 1-antitrypsin).. Calprotectin and lactoferrin concentrations increased significantly during radiation treatment (P = 0.0005 and P = 0.019). Transferrin was detected in only 9 out of 45 samples. There were no changes in tumour necrosis factor alpha (TNF alpha), leukotriene B4, prostaglandin E2 and thromboxane B2 during treatment. alpha 1-antitrypsin could not be detected in any sample.. This study indicates that faecal calprotectin and lactoferrin concentrations could be markers of acute, radiation-induced proctitis. Patient compliance and stability of the markers make this a promising method for clinical research. Eicosanoids could be measured in stool samples, but the concentrations did not increase with increasing radiation dose.

Topics: Acute Disease; Aged; alpha 1-Antitrypsin; Biomarkers; Dinoprostone; Enzyme-Linked Immunosorbent Assay; Feces; Humans; Lactoferrin; Leukocyte L1 Antigen Complex; Leukotriene B4; Male; Middle Aged; Pilot Projects; Proctitis; Prostatic Neoplasms; Radiation Injuries; Transferrin; Tumor Necrosis Factor-alpha

Diets high in fat are associated with an increased risk of prostate cancer, although the molecular mechanism is still unknown. We have previously reported that arachidonic acid, an omega-6 fatty acid common in the Western diet, stimulates proliferation of prostate cancer cells through production of the 5-lipoxygenase metabolite, 5-HETE (5-hydroxyeicosatetraenoic acid). We now show that 5-HETE is also a potent survival factor for human prostate cancer cells. These cells constitutively produce 5-HETE in serum-free medium with no added stimulus. Exogenous arachidonate markedly increases the production of 5-HETE. Inhibition of 5-lipoxygenase by MK886 completely blocks 5-HETE production and induces massive apoptosis in both hormone-responsive (LNCaP) and -nonresponsive (PC3) human prostate cancer cells. This cell death is very rapid: cells treated with MK886 showed mitochondrial permeability transition between 30 and 60 min, externalization of phosphatidylserine within 2 hr, and degradation of DNA to nucleosomal subunits beginning within 2-4 hr posttreatment. Cell death was effectively blocked by the thiol antioxidant, N-acetyl-L-cysteine, but not by androgen, a powerful survival factor for prostate cancer cells. Apoptosis was specific for 5-lipoxygenase-programmed cell death was not observed with inhibitors of 12-lipoxygenase, cyclooxygenase, or cytochrome P450 pathways of arachidonic acid metabolism. Exogenous 5-HETE protects these cells from apoptosis induced by 5-lipoxygenase inhibitors, confirming a critical role of 5-lipoxygenase activity in the survival of these cells. These findings provide a possible molecular mechanism by which dietary fat may influence the progression of prostate cancer.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Antineoplastic Agents; Apoptosis; Cell Membrane; Dietary Fats; Drug Combinations; Drugs, Chinese Herbal; Flavanones; Flavonoids; Glycyrrhiza; Humans; Hydroxyeicosatetraenoic Acids; Ibuprofen; Indoles; Leukotriene B4; Lipoxygenase Inhibitors; Male; Mitochondria; Models, Biological; Nucleosomes; Oxidative Stress; Paeonia; Permeability; Phosphatidylserines; Prostatic Neoplasms; Tumor Cells, Cultured

When human PC-3 cells derived from a metastatic prostatic adenocarcinoma were incubated for 15 min to 4 h with the in vitro inhibitor of eicosanoid biosynthesis, eicosatetraynoic acid (ETYA) at 10-80 microM, DNA synthesis was suppressed. No reduction in cellular viability occurred, as judged by exclusion of trypan blue or unaltered release of 51Cr-labeled proteins, and the inhibition was partially reversible. Indomethacin (to 12.5 micrograms/ml) did not inhibit DNA synthesis or alter the suppression of DNA synthesis by ETYA, suggesting a role for a lipoxygenase product in this effect. Addition of leukotriene B4 (LTB4) at 10(-8) M did not reverse the inhibition of DNA synthesis produced by ETYA, nor did arachidonic acid (10(-5) - 10(-9) M) incubated with control cells mimic the effect of that agent. 3H-arachidonic acid incubated with PC-3 cells was rapidly incorporated into phospholipids and this labeling was differentially inhibited by ETYA. Positive modulation of PC-3 cellular DNA synthesis by lipoxygenase products and inhibition of their synthesis by ETYA is one attractive hypothesis with which to account for these results. Other consequences of producing a selective deficiency of arachidonic acid in cellular membrane phospholipids and even the probable substitution of ETYA for arachidonic acid could also contribute to the inhibition of DNA synthesis by ETYA.

Topics: 5,8,11,14-Eicosatetraynoic Acid; Adenocarcinoma; Arachidonic Acid; Arachidonic Acids; Calcimycin; Cyclooxygenase Inhibitors; DNA; Fatty Acids, Unsaturated; Humans; Indomethacin; Leukotriene B4; Lipoxygenase Inhibitors; Male; Phospholipids; Prostatic Neoplasms; Tumor Cells, Cultured